Showing papers in "Journal of Biomolecular Structure & Dynamics in 2023"

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology.

Abstract: The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.

Anticancer potential of Cu(II)prolinedithiocarbamate complex: design, synthesis, spectroscopy, molecular docking, molecular dynamic, ADMET, and in-vitro studies.

Abstract: Breast cancer continues to be a major health issue for women all over the world. Cancer medications like cisplatin, which are widely used, still have negative side effects. The novel complex was created as a potential anticancer medication candidate that is both effective and safe, with few side effects. The Cu(II) complex using the prolinedithiocarbamate ligands was synthesized in situ. The Cu(II) complexes Characterization by UV-Vis, FT-IR spectroscopy and melting point determination, conductivity, and HOMO-LUMO were studied. Computational NMR spectrum analysis was performed. The interaction of Cu(II)prolineditiocarbamate complex with cancer cell target protein (MCF-7) was confirmed by molecular docking and molecular dynamic. The pharmacokinetic/ADMET properties were also performed on the complex. Results of the cytotoxic complex test against cancer cells (MCF-7) undergoing apoptosis with an IC50 value of 13.64 µg/mL showed high anticancer activity in MCF-7 cancer cells. The in-vivo data for Cu(II)prolineditiocarbamate complex was predicted using the Protox online tool with an LD50 value of 2500 mg/kg and belonging to the GHS toxicity class 5, which means the compound has a low acute toxicity effect. The Cu(II) prolineitiocarbamate complex may pave the way for the development of essential metal-based chemotherapy for the treatment of breast cancer.Communicated by Ramaswamy H. Sarma.

Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor.

Abstract: A class of 2-(1H-imidazol-1-yl)-1-phenylethyl cinnamates 6a-6j and 2-(1H-benzo[d]imidazol-1-yl)-1-phenylethyl cinnamates 7a-7j were synthesized, and their synthesis was validated using various spectroscopic techniques like IR, NMR, and Mass spectrometry. In addition, the compounds were assessed for in-vitro antibacterial against gram-positive and gram-negative strains and in-vitro antifungal against six different fungal strains. Compounds 6 g, 7 b, 7f, and 7 g exhibited significant activity against all bacterial strains ranging from MIC = 12.5-50 µg/mL, and compounds 6 g, 7 b, and 7 g exhibited considerable activity against all fungal strains ranging from MFC = 125-200 µg/mL. A molecular docking study indicated that compounds 6 g, 7 b, 7 g, and 7j could be lodged in the active pocket and inhibit C. albicans Sterol 14α-demethylase (CYP51) protein via various interactions, and these studies validate the antifungal results. Different parameters from the 100 ns MD simulation study are investigated to evaluate the dynamic stability of protein-ligand complexes. According to the MD simulation study, the proposed compounds effectively kept their molecular interaction and structural integrity within the C. albicans Sterol 14-demethylase. Compounds 6 g, 7 b, and 7 g are promising lead compounds in searching for novel antifungal drug-like molecules. Furthermore, in silico ADME indicates that these compounds possess drug-like physicochemical properties to be orally bioavailable.Communicated by Ramaswamy H. Sarma.

Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies.

Abstract: c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2.Communicated by Ramaswamy H. Sarma.

Design of novel anti-cancer drugs targeting TRKs inhibitors based 3D QSAR, molecular docking and molecular dynamics simulation.

Abstract: Tropomyosin receptor kinase (TRK) enzymes are responsible for different types of tumors caused by neurotrophic tyrosine receptor kinase gene fusion and have been identified as an effective target for anticancer therapy. The study of the mechanism between polo-like kinase (PLKs) and pyrazol inhibitors was performed using 3D-QSAR modeling, molecular docking, and MD simulations in order to design high-activity inhibitors. The HQSAR (Q2 = 0.793, R2 = 0.917, R2ext = 0.961), CoMFA (Q2 = 0.582, R2 = 0.722, R2ext = 0.951), CoMSIA/SE (Q2 = 0.603, R2 = 0.801, R2ext = 0.849), and Topomer CoMFA (Q2 = 0.726, R2 = 0.992, R2ext = 0.717) showed good reliability and predictability. All models have been successfully tested by external validation, so all five established models are reliable. The analysis of the different contour maps of different models gives structural information to improve the inhibitory function. Molecular docking results show that the amino acids Met 592, GLU 590, LEU 657, VAL 524, and PHE 589 are the active sites of the tropomyosin receptor TRKs. The results obtained by MD showed that compound 19i could form a more stable complex protein (PDB id: 5KVT). Based on these results, we developed new compounds and their expected inhibitory activities. The results of physicochemical and ADME-Tox properties showed that the four proposed molecules are orally bioavailable, and they are not toxic in the Ames test. Thus, these results would provide modeling information that could help experimental researchers find TRK type I inhibitors more efficiently.Communicated by Ramaswamy H. Sarma.

Design, synthesis, anti-acetylcholinesterase evaluation and molecular modelling studies of novel coumarin-chalcone hybrids.

Abstract: The major enzyme responsible for the hydrolytic breakdown of the neurotransmitter acetylcholine (ACh) is acetylcholinesterase (AChE). Acetylcholinesterase inhibitors (AChEIs) are the most prescribed class of medications for the treatment of Alzheimer's disease (AD) and dementia. The limitations of available therapy, like side effects, drug tolerance, and inefficacy in halting disease progression, drive the need for better, more efficacious, and safer drugs. In this study, a series of fourteen novel chalcone-coumarin derivatives (8a-n) were designed, synthesized and characterized by spectral techniques like FT-IR, NMR, and HR-MS. Subsequently, the synthesized compounds were tested for their ability to inhibit acetylcholinesterase (AChE) activity by Ellman's method. All tested compounds showed AChE inhibition with IC50 value ranging from 0.201 ± 0.008 to 1.047 ± 0.043 μM. Hybrid 8d having chloro substitution on ring-B of the chalcone scaffold showed relatively better potency, with IC50 value of 0.201 ± 0.008 μM compared to other members of the series. The reference drug, galantamine, exhibited an IC50 at 1.142 ± 0.027 μM. Computational studies revealed that designed compounds bind to the peripheral anionic site (PAS), the catalytic active site (CAS), and the mid-gorge site of AChE. Putative binding modes, ligand-enzyme interactions, and stability of the best active compound are studied using molecular docking, followed by molecular dynamics (MD) simulations. The cytotoxicity of the synthesised derivatives was determined using the MTT test at three concentrations (100 g/mL, 500 g/mL, and 1 mg/mL). None of the chemicals had a significant effect on the body at the highest dose of 1 mg/mL.Communicated by Ramaswamy H. Sarma.

Identification of potent EGFR-TKD inhibitors from NPACT database through combined computational approaches.

Abstract: Cancer is the world's second leading cause of death, and there are no approved herbal therapies. The epidermal growth factor receptor tyrosine kinase (EGFR-TK) receptor is a transmembrane protein with eight domains that is found in almost every cancer type and plays an important role in abnormal cell cellular function and causes malignant outcomes. The current study aimed to virtually screen phytochemicals from the NPACT database against EGFR-TKD and also to identify potential inhibitors of this transmembrane protein among plant candidates for anticancer drug development. The docking scores of the chosen phytochemicals were compared with the control (erlotinib). Kurarinone, (2S)-2-methoxykurarnione, and Sophoraflavanone-G exhibited a stronger binding affinity of -18.102 kcal/mol, -14.243 kcal/mol, and -13.759 kcal/mol than erlotinib -12.783 kcal/mol. Moreover, several online search engines were used to predict ADME and toxicity. The drug-likeness of selected phytochemicals was higher than the reference (erlotinib). A 100 ns molecular dynamic (MD) simulation was also applied to the docked conformations to examine the stability and molecular mechanics of protein-ligand interactions. Furthermore, the calculated molecular mechanics Poisson Boltzmann surface area energy of (2S)-2-methoxykurarnione was found to be -129.555 ± 0.512 kJ/mol, which approximately corresponds to the free energy of the reference molecule -130.595 ± 0.908 kJ/mol. We identify phytoconstituents present in Sophora flavescens from the NPACT database, providing key insights into tyrosine kinase inhibition and may serve as better chemotherapeutic agents. Experimental validation is required to determine the anti-EGFR potency of the potent lead molecules discussed in this study.Communicated by Ramaswamy H. Sarma.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations.

Abstract: Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

Computational approaches to define poncirin from Magnolia champaka leaves as a novel multi-target inhibitor of SARS-CoV-2.

Abstract: Phytochemical-based drug discovery against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been the focus of the current scenario. In this context, we aimed to perform the phytochemical profiling of Magnolia champaka, an evergreen tree from the Magnoliaceae family, in order to perform a virtual screening of its phytoconstituents against different biological targets of SARS-CoV-2. The phytochemicals identified from the ethanol extract of M. champaka leaves using liquid chromatography-mass spectroscopy (LC-MS) technique were screened against SARS-CoV-2 spike glycoprotein (PDB ID: 6M0J), main protease/Mpro (PDB ID: 6LU7), and papain-like protease/PLpro (PDB ID: 7CMD) through computational tools. The experimentation design included molecular docking simulation, molecular dynamics simulation, and binding free energy calculations. Through molecular docking simulation, we identified poncirin as a common potential inhibitor of all the above-mentioned target proteins. In addition, molecular dynamics simulations, binding free energy calculations, and PCA analysis also supported the outcomes of the virtual screening. By the virtue of all the in silico results obtained, poncirin could be taken for in vitro and in vivo studies in near future.Communicated by Ramaswamy H. Sarma.

Molecular recognition of bio-active triterpenoids from Swertia chirayita towards hepatitis Delta antigen: a mechanism through docking, dynamics simulation, Gibbs free energy landscape.

Abstract: Medicinal plants the underpinning of indigenous herbal serve, are the possible source of key compounds for the development of new drugs. Hepatitis D, one of the most widespread infectious diseases associated with global public health issues. Therefore, we aim to screen natural compounds to find out potent inhibitor towards hepatitis delta antigen. Through ADMET investigation, we have screened twenty phytochemicals for this study. Additionally, using molecular docking, these phytochemicals were docked with the HDV protease which signifies the phytochemicals beta-amyrin, chiratenol, episwertenol and swertanone have a significant capability to bind with hepatitis D virus protein. The docking study was further accompanied by analyzes RMSD, RMSF, Rg, SASA, Hbond number, and principal component analysis through 100 ns MD simulations. Based on our principal component analysis, beta-amyrin, chiratenol, episwertenol and swertanone phytochemicals can be a potential drug candidates for inhibition of hepatitis D. The above observation is also supported by our Gibbs free energy landscape study. The potential therapeutic characteristics of the phytochemicals against hepatitis D inhibition offer additional support for the in vitro and in vivo studies in future. Communicated by Ramaswamy H. Sarma.

Investigation on the mechanisms by which the herbal remedies induce anti-prostate cancer activity: uncovering the most practical natural compound.

Abstract: Prostate cancer (PCa) is one of the most reported cancers among men worldwide. Targeting the essential proteins associated with PCa could be a promising method for cancer treatment. Traditional and herbal remedies (HRs) are the most practical approaches for PCa treatment. Here, the proteins and enzymes associated with PCa were determined based on the information obtained from the DisGeNET database. The proteins with a gene-disease association (GDA) score greater than 0.7 and the genes that have a disease specificity index (DSI) = 1 were selected as the target proteins. 28 HRs with anti-PCa activity as a traditional treatment for PCa were chosen as potential bioactive compounds. More than 500 compound-protein complexes were screened to find the top-ranked bioactives. The results were further evaluated using the molecular dynamics (MD) simulation and binding free energy calculations. The outcomes revealed that procyanidin B2 3,3'-di-O-gallate (B2G2), the most active ingredient of grape seed extract (GSE), can act as an agonist for PTEN. PTEN has a key role in suppressing PCa cells by applying phosphatase activity and inhibiting cell proliferation. B2G2 exhibited a considerable binding affinity to PTEN (11.643 kcal/mol). The MD results indicated that B2G2 could stabilize the key residues of the phosphatase domain of PTEN and increase its activity. Based on the obtained results, the active ingredient of GSE, B2G2, could play an agonist role and effectively increase the phosphatase activity of PTEN. The grape seed extract is a useful nutrition that can be used in men's diets to inhibit PCa in their bodies.Communicated by Ramaswamy H. Sarma.

Exploring quantum computational, molecular docking, and molecular dynamics simulation with MMGBSA studies of ethyl-2-amino-4-methyl thiophene-3-carboxylate

Abstract: 2-aminothiophenes derivative, Ethyl-2-amino-4-methyl thiophene-3-carboxylate (EAMC) has been synthesized, characterized, and investigated quantum chemically. It was experimentally investigated by different spectroscopic methods like- NMR (1H-NMR and 13C-NMR), FT-IR, and UV-Visible. B3LYP method and 6-311++G(d,p) basis set were employed for optimization of molecular structure and calculation of wave numbers of normal modes of vibrations and various other important parameters. Calculated bond lengths and angles were compared with the experimental bond lengths and Bond Angle Parameters. Optimized bond parameters and experimental bond parameters were found in good agreement. Complete potential energy distribution assignments were done successfully by VEDA. The HOMO/LUMO energy gap emphasizes adequate charge transfer happening within the molecule. A study of donor-acceptor interconnections was done via NBO analysis. MEP surface analysis was done to demonstrate charge distribution and reactive areas qualitatively in the molecule. The degree of relative localization of electrons was analyzed via ELF Diagram. The Fukui function analysis showed possible sites for attacks by different substituents. By using the TD-DFT method and PCM solvent model, the UV–Vis spectrum (gas, methanol, DMSO) and the maximum absorption wavelength was computed and compared with experimental data. 3D and 2D intermolecular interactions in the crystal were analyzed via Hirshfeld surface analysis and fingerprint plots reveal that the EAMC crystal was stabilized by H–-H/H–-H/C–-H bond formation. The molecular docking was done with 7 different protein receptors on the molecule to find the best ligand-protein interactions. Molecular dynamic simulations and MMGBSA calculations were also carried out to find out the best binding of the ligand with the protein.Communicated by Ramaswamy H. Sarma

Design, synthesis, anticancer evaluation, in silico docking and ADMET analysis of novel indole-based thalidomide analogs as promising immunomodulatory agents.

Abstract: In the present work, novel 16 indole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3 and MCF-7 cell lines. Generally, the opened analogs of glutarimide ring exhibited higher activities than the closed ones. Compounds 21a-b and 11d,g showed strong potencies against all tested cell lines with IC50 values ranging from 8.27 to 25.20 µM comparable to that of thalidomide (IC50 values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 11g, 21a and 21b showed remarkable significant reduction in TNF-α. Furthermore, compounds 11g, 21a and 21b showed significant elevation in CASP8 levels. Compounds 11g and 21a significantly inhibited VEGF. In addition, derivatives 11d, 11g and 21a showed significant decrease in level of NF-κB p65. Moreover, our derivatives exhibited good in silico docking and ADMET profile.Communicated by Ramaswamy H. Sarma.

A computational investigation of galactopyranoside esters as antimicrobial agents through antiviral, molecular docking, molecular dynamics, pharmacokinetics, and bioactivity prediction.

Abstract: One of the most common viral infections worldwide is the Human Papilloma Virus (HPV) which has been linked to cancer and other diseases in many countries. Monosaccharide esters are significant in the field of carbohydrate chemistry because they are efficient in the synthesis of pharmacologically active compounds. Therefore, the present study aimed to perform thermodynamic, molecular docking and molecular dynamics study of a series of previously designed monosaccharaides, methyl β-d-galactopyranoside (MGP, 1) esters (2-10) with along with their physicochemical and pharmacokinetic properties. We have optimized the MGP esters employing the DFT study at the B3LYP/6-311 + G (d,p) level of theory. The subsequent analysis also investigated the electronic energies, enthalpies, entropies, polarizability, and natural bond orbital (NBO) of these modified esters. Then, MGP esters were docked into CTX-M-15 extended-spectrum beta-lactamase from Escherichia coli (PDB: 4HBT) and E2 DNA-binding domain from human papillomavirus type 31 (PDB: 1A7G), and the results revealed that most of the esters can efficiently bind to the target. Desmond was used to doing molecular dynamics simulations at 200 ns in addition to molecular docking to look at the binding conformational stability of the protein-ligand complex. Based on RMSD and RMSF, it was determined that the stability of the protein-ligand combination was maintained during the whole 200 ns simulations for all compounds. Finally, a pharmacokinetic study suggests that modified esters of MGP exhibited better pharmacokinetic characteristics and were less hazardous than the parent drug. This work demonstrated that potential MGP esters can efficiently bind to 4HBT and 1A7G proteins and opened avenues for the development of newer antimicrobial agents that can target dangerous pathogens.Communicated by Ramaswamy H. Sarma.

Design, synthesis, spectroscopic characterizations, single crystal X-ray analysis, in vitro xanthine oxidase and acetylcholinesterase inhibitory evaluation as well as in silico evaluation of selenium-based N-heterocyclic carbene compounds.

Abstract: Herein, eight new NHC-based selenourea derivatives were synthesized and characterized by using spectroscopic method (1H, 19F, and 13C NMR, FT-IR), and elemental analysis techniques. These compounds were synthesized by mixing benzimidazolium salts, potassium carbonate, and selenium powder in ethyl alcohol. Additionally, the molecular and crystal structures of the three compounds (1c, 2b, and 2c) were determined using the single-crystal x-ray diffraction (XRD) method. Diffraction analysis demonstrated the partial carbon-selenium double-bond character of these compounds. All compounds were determined to be highly potent inhibitors for AChE and XO enzymes. The IC50 values for the compounds were found in the range of 0.361-0.754 μM for XO and from 0.995 to 1.746 μM for AChE. The DNA binding properties of the compounds were investigated. These compounds did not have a remarkable DNA binding property. Also, DPPH radical scavenging activities of the compounds were also investigated. Compounds (1c), (2a), (3a), and (3b) exhibited more pronounced DPPH radical scavenging activity when compared to other compounds. Docking studies were applied by using AutoDock 4 to determine interaction mechanism of the selected compounds (1a), (1b), and (3b). The compound (1b) has good binding affinity (-9.78 kcal/mol) against AChE, and (-6.86 kcal/mol) for XO target. Drug similarity properties of these compounds compared to positive controls were estimated and evaluated by ADMET analysis. Furthermore, molecular dynamics simulations have been applied to understand the accuracy of docking studies. These findings and the defined compounds could be potential candidates for the discovery and progress of effective medicine(s) for AChE and XO in the future.Communicated by Ramaswamy H. Sarma.

Field and atom-based 3D-QSAR models of chromone (1-benzopyran-4-one) derivatives as MAO inhibitors.

Abstract: Monoamine oxidases (MAOs) are flavo-enzymes that aid in the oxidative deamination of neurotransmitters like dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that work by preventing the breakdown of brain neurotransmitters and regulating mood. MAO inhibitors that use the chromone (1-benzopyran-4-one) structure have been found to be quite effective in studies. The current study involves the creation of pharmacophore models, 3-D QSAR, virtual screening, and docking investigations, all of which are evaluated using various criteria. The investigation included 39 ligands that emerged pharmacophore AHRRR_1, as the best pharmacophore model with a survival score of 5.6485. The 3D QSAR investigation revealed a significant model with the values of R2 = 0.9064 and Q2 = 0.8239. Docking study revealed that compound 18 had the highest docking (-10.402 kcal/mol) score in the series and showed interactions with the essential amino acid TYR398 required for MAO inhibitory activity. ZINC compounds were screened using the created pharmacophore model, which was followed up with a virtual screening study. The ZINC compounds with the best XP docking scores are ZINC03113255, ZINC07777127, ZINC05166353 and ZINC09341502 (with docking scores -10.021, -9.486, -8.031 and -7.792 kcal/mol, respectively). ZINC03113255, which showed the best score, has binding interactions with amino acid residues, TYR326, TYR398 and LYS296 of monoamine oxidase B. The ADME analysis demonstrated the compound's drug-like characteristics. The findings of this study may be used in the development of chromone compounds that target the MAO inhibitor. Communicated by Ramaswamy H. Sarma.

Paradoxical effect of Aβ on protein levels of ABCA1 in astrocytes, microglia, and neurons isolated from C57BL/6 mice: an in vitro and in silico study to elucidate the effect of Aβ on ABCA1 in the brain cells.

Abstract: Impaired cholesterol metabolism has been reported in Alzheimer's disease. Since ABCA1 is one of the main players in the brain's cholesterol homeostasis, here we used the in-vitro and in-silico experiments to investigate the effect of Aβ on ABCA1 protein levels in microglia, astrocytes, and neurons in mice. Microglia, astrocytes, and neurons were cultured and exposed to beta amyloid. ABCA1 in cell lysates was determined by Western blotting, and cholesterol efflux was measured in the conditioned media. Molecular docking, molecular dynamics simulations, and MM-GBSA analysis were conducted to gain a better understanding of the effects of Aβ on ABCA1. In response to Aβ, the protein levels of ABCA1 increase significantly in microglia, astrocytes, and neurons; however, its ability to enhance cholesterol efflux is diminished. Aβ inhibited the function of ABCA1 by obstructing the extracellular tunnel that transports lipids outside the cell, as determined by molecular docking. MD simulation analysis validated these findings. Our results demonstrated that Aβ could increase ABCA1 protein levels in various brain cells, regardless of cell type. Molecular docking, molecular dynamics simulation, and MM-GBSA studies indicate that Aβ has a significant effect on the structural conformation of ABCA1, possibly interfering with its function. We believe that the conformational changes of ABCA1 will inhibit its ability to subsequently release cellular cholesterol. Aβ may obstruct the extracellular tunnel of ABCA1, rendering it less accessible to proteases such as the calpain family, which may explain the increase in ABCA1 levels but decrease in its function.Communicated by Ramaswamy H. Sarma.

Acetylcholinesterase inhibition of Alzheimer's disease: identification of potential phytochemicals and designing more effective derivatives to manage disease condition.

Abstract: Alzheimer's disease (AD) is a brain disease characterized by gradual memory loss and cognitive impairments. Acetylcholinesterase (AChE) inhibitors-such as donepezil, memantine, and tacrine-are FDA-approved medications for AD treatment. Due to the lack of their efficacy and higher side effects, many researchers have been searching for effective and safer alternatives. In this study, experimentally proved phytochemicals against brain diseases were screened based on their binding energies to the target site of AChE, pharmacokinetic properties, and drug-likeness. Although some phytochemicals showed higher binding affinities than the control drug (donepezil), they did not show permeability across the blood-brain barrier (BBB). However, berberine, anthocyanin, and diterpene alkaloid can cross the BBB and showed good binding affinities of -10.3, -10.1, and -10.2 kcal/mol, respectively. MD simulation and PCA of the simulation data of the protein and protein-ligand complexes proved that the complexes are stable in the biological environment. A total of 16 derivatives of berberine and 3 derivatives of anthocyanin also showed higher binding energies compared to the binding affinity (-11.5 kcal/mol) of the donepezil. The derivatives were designed by substituting -F, -CF3, -CN, and -NH2, and provided higher docking scores due to increasing of nonbonding interactions. MM/GBSA calculations show that the binding free energies of the best predicted derivatives of diterpene alkaloid, anthocyanin, and berberine (DA22, AC11, and BB40) are -100.4 ± 8.4, -79.3 ± 8.7, and -78.3 ± 10.7 kcal/mol, respectively, with the protein. Overall, this study was successful in finding new, highly effective, and possibly safer inhibitors of AChE. Communicated by Ramaswamy H. Sarma.

Allosteric modulation of conserved motifs and helices in 5HT2BR: Advances drug discovery and therapeutic approach towards drug resistant epilepsy.

Abstract: The 5HT2BR, class-A GPCR is a new target, and its significance for seizure reduction in Dravet syndrome is just now gaining interest, suggesting its specific role in epileptic seizure management. Homology modeling of human 5HT2BR (P41595), was performed using a template 4IB4, the modeled structure was cross-validated (stereo chemical hindrance, Ramachandran plot, enrichment analysis) to mimic a closer native structure. Virtual screening (8532 compounds), drug-likeliness, mutagenicity, and carcinogenicity profiling prioritized six compounds for molecular dynamics (500 ns), Rgyr, DCCM. The receptor's C-alpha fluctuation upon bound agonist (6.91 Å), known antagonist (7.03 Å), and LAS 52115629 (5.83 Å) binding varies, leading to receptor stabilization. The residues C-alpha side-chain in active site strongly interacts (hydrogen bonds) with bound agonist (100% interaction: ASP135), known antagonist (95%:ASP135), and LAS 52115629 (100%:ASP135). The Rgyr for receptor-ligand complex, LAS 52115629 (25.68 Å), lies close to bound agonist-Ergotamine, and DCCM analysis also shows strong positive correlations for LAS 52115629 as compared to known drugs. LAS 52115629 is less likely to cause toxicity than known drugs. The structural parameters in the modeled receptor's conserved motifs (DRY, PIF, NPY) were altered for receptor activation upon ligand-binding, which otherwise was in the in-activated state. The ligand (LAS 52115629)-binding further alters the helices-III, V, VI (G-protein bound), and VII, which form potential interacting sites with the receptor and are proven necessary for activating the receptor. Therefore, LAS 52115629 can act as a potential 5HT2BR agonist, targeting drug-resistant epilepsy.Communicated by Ramaswamy H. Sarma.

The switch states of the GDP-bound HRAS affected by point mutations: a study from Gaussian accelerated molecular dynamics simulations and free energy landscapes.

Abstract: Point mutations play a vital role in the conformational transformation of HRAS. In this work, Gaussian accelerated molecular dynamics (GaMD) simulations followed by constructions of free energy landscapes (FELs) were adopted to explore the effect of mutations D33K, A59T and L120A on conformation states of the GDP-bound HRAS. The results from the post-processing analyses on GaMD trajectories suggest that mutations alter the flexibility and motion modes of the switch domains from HRAS. The analyses from FELs show that mutations induce more disordered states of the switch domains and affect interactions of GDP with HRAS, implying that mutations yield a vital effect on the binding of HRAS to effectors. The GDP-residue interaction network revealed by our current work indicates that salt bridges and hydrogen bonding interactions (HBIs) play key roles in the binding of GDP to HRAS. Furthermore, instability in the interactions of magnesium ions and GDP with the switch SI leads to the extreme disorder of the switch domains. This study is expected to provide the energetic basis and molecular mechanism for further understanding the function of HRAS.Communicated by Ramaswamy H. Sarma.

Bioisosteric modification of Linezolid identified the potential M. tuberculosis protein synthesis inhibitors to overcome the myelosuppression and serotonergic toxicity associated with Linezolid in the treatment of the multi-drug resistance tuberculosis (MDR-TB).

Abstract: Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against M. tuberculosis and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (3071, 7549 and 9660) as less toxic potential modulators of Mtb EthR protein. Compounds 3071, 7549 and 9660 were having the significant docking score of -12.696 Kcal/mol, -12.681 Kcal/mol and -15.293 Kcal/mol towards the Mtb EthR protein with less MAO-A and B affinity [compound 3071: MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound 7549: MAO A (> -2.00 Kcal/mol) and MAO B (> -2.00 Kcal/mol) and compound 9660: MAO A (> -5.678 Kcal/mol) and MAO B (> -6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid.Communicated by Ramaswamy H. Sarma.

In vitro anticancer, antioxidant and enzyme inhibitory potentials of endemic Cephalaria elazigensis var. purpurea with in silico studies.

Abstract: In this study, the therapeutic potential and phytochemical composition of ethanolic extract of Cephalaria elazigensis var. purpurea (CE), an endemic species, were investigated. For this purpose, the antiproliferative effect of CE on the MCF-7 human breast cancer cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and its effectiveness on colony formation and cell migration was analyzed with clonogenic assay and wound healing assay, respectively. In addition, the cell death detection ELISA (CDDE) assay was conducted to determine the pro-apoptotic capacity of CE. The IC50 value of the CE was determined as 324.2 ± 14.7 µg/mL. Furthermore, upon 1000 µg/mL CE treatment, there was 4.96-fold increase in the population of cells undergoing apoptosis compared to the untreated control cells. The antioxidant activity tests were performed by DPPH free radical, ABTS cation radical, ferric-ion reducing power (FRAP) and ferrous-ion chelating power (FCAP) assays. Antioxidant activity values for the DPPH, ABTS and FRAP assays were found to be 125.6 ± 6.3, 34.09 ± 0.1 and 123.4 ± 4.2 µmol TE/mg DE, respectively. We further determined the effect of CE ethanolic extract against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. CE plays an effective inhibitory role in AChE and BuChE (AChE: IC50: 10.54 µg/mL, BuChE: IC50: 6.84 µg/mL) respectively. Further, molecular docking stuy was conducted to understand the nature of the all compound against AChE an BChE. It is revealed that α-Linolenic acid shows lowest binding energy (-7.90 kcal/mol) towards AChE, on the other side, Linoleic acid shows good binding affinity (-7.40 kcal/mol) for BChE.Communicated by Ramaswamy H. Sarma.

Interactions between β-cyclodextrin as a carrier for anti-cancer drug delivery: a molecular dynamics simulation study.

Abstract: A series of molecular dynamics simulations were performed on 5-fluorouracil (5-Fu), Alendronate (Ald), and Temozolomide (TMZ) anticancer drugs in the presence and absence of β-cyclodextrin (βCD) as a carrier. Thermodynamic investigations showed that the van der Waals interaction energy was dominant in loading all drugs inside the βCD cavity. The sum of the interaction energies illustrated that the highest affinity was related to Ald (-136.5 kJ/mol), which in turn was due to the presence of bulky and charged atoms of phosphorus and oxygen, although TMZ (-115.92 kJ/mol) showed a very high affinity as well. At the same time, the hydrogen bond analysis also represented that Ald had the most hydrogen bond (1.97) with the highest half-life (3.13 ps) with βCD. Investigation of the root mean fluctuation (RMSF) indicated that all the drugs had a relatively rigid structure and maintain this rigidity during loading in the βCD cavity, and in the meantime, Ald was slightly more flexible than 5-Fu and TMZ. The area of ​the primary hydroxyl rim decreased in all drug-containing systems, which in turn was caused by the attractive interaction of drugs with oxygens in the primary hydroxyl rim. Especially for those drugs that were able to penetrate to the end of the primary hydroxyl rim of the βCD, that means TMZ and 5-Fu. Meanwhile, due to the lack of Ald penetration to the end of the primary hydroxyl rim, the area change in the Ald-containing system was less than in the two others.Communicated by Ramaswamy H. Sarma.

Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques.

Abstract: A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA (Q2 = 0.689; R = 0.999; R2pred = 0.986), CoMSIA (Q2 = 0.614; R2 = 0.923; R2pred = 0.815) and HQSAR (Q2= 0.603; R2 = 0.662; R2pred = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC50 inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma.

Network pharmacology- and molecular simulation-based exploration of therapeutic targets and mechanisms of heparin for the treatment of sepsis/COVID-19.

Abstract: Critically infected patients with COVID-19 (coronavirus disease 2019) are prone to develop sepsis-related coagulopathy as a result of a robust immune response. The mechanism underlying the relationship between sepsis and COVID-19 is largely unknown. LMWH (low molecular weight heparin) exhibits both anti-inflammatory and anti-coagulating properties that result in a better prognosis of severely ill patients with COVID-19 co-associated with sepsis-induced coagulopathy or with a higher D-dimer value. Heparin-associated molecular targets and their mechanism of action in sepsis/COVID-19 are not well understood. In this work, we characterize the pharmacological targets, biological functions and therapeutic actions of heparin in sepsis/COVID-19 from the perspective of network pharmacology. A total of 38 potential targets for heparin action against sepsis/COVID-19 and 8 core pharmacological targets were identified, including IL6, KNG1, CXCL8, ALB, VEGFA, F2, IL10 and TNF. Moreover, enrichment analysis showed that heparin could help in treating sepsis/COVID-19 through immunomodulation, inhibition of the inflammatory response, regulation of angiogenesis and antiviral activity. The pharmacological effects of heparin against these targets were further confirmed by molecular docking and simulation analysis, suggesting that heparin exerts effective binding capacity by targeting the essential residues in sepsis/COVID-19. Prospective clinical practice evaluations may consider the use of these key prognostic indicators for the treatment of sepsis/COVID-19.Communicated by Ramaswamy H. Sarma.

In silico discovery of potent inhibitors against monkeypox's major structural proteins.

Abstract: Monkeypox virus (MPXV) outbreak in non-endemic countries is a worldwide public health emergency. An enveloped double-stranded DNA virus belongs to the genus Orth poxvirus. A viral zoonotic infection known as monkeypox has been a serious risk to public health, especially in Africa. However, it has recently spread to other continents, so it might soon become a worldwide problem. There is an increased risk of transmission of the virus because there is a lack of effective treatment that cures the disease. To stop the multi-country outbreak from spreading, it is important to discover effective medications urgently. The objective of the current study is to swiftly find new treatments for the monkeypox virus using advanced computational approaches. By investigating five potential MPXV targets (DNA ligase, Palmytilated Extracellular Enveloped Virus (EEV) membrane protein, Scaffold protein D13, Thymidylate Kinase, and Viral core cysteine proteinase), this research was carried out using cutting-edge computational techniques against human monkeypox virus infection. Here we present the accurate 3D structures and their binding cavities of the selected targets with higher confidence using AlphaFold 2 and SiteMap analysis. Molecular docking and MD simulation analysis revealed the top five potential lead compounds with higher binding affinity and stability toward selected targets. Binding free energy calculations and other essential dynamics analysis supports the finding. The selected lead compounds utilizing virtual screening and drug repurposing approach reported in this study are beneficial for medical scientists and experimental biologists in drug development for the treatment of human MPXV.Communicated by Ramaswamy H. Sarma.

Discovery of potential phytochemicals as inhibitors of TcdB, a major virulence factors of Clostridioides difficile.

Abstract: Clostridioides difficile is a gram-positive bacterium which is associated with different gastrointestinal related infections, and the numbers of cases related to it are continuously increasing in the past few years. Owing to high prevalence and development of resistance towards available antibiotics, it is required to develop new therapeutics to combat C. difficile infection. The current study was aimed to identify novel phytochemicals that could bind and inhibits the TcdB, an exotoxin which is required for the pathogenesis of bacteria, and hence can be considered as the future drug candidates against C. difficile. ∼2500 therapeutically important phyto-compounds were docked against the active sites of TcdB protein by using AutoDock-Vina software. The interactions between the ligands and the binding site of the top five docked complexes, based on the docking scores, were further elucidated by Molecular Dynamics Simulations of 500 ns, Molecular Mechanics Energies combined with the Poisson-Boltzmann and Surface Area (MMPBSA) or Generalized Born and Surface Area (MMGBSA), and WaterSwap Analysis. Findings of molecular docking suggested that natural compounds A183, A704, A1528, A2083, and A2129 with distinct chemical scaffolds are best docked in the binding site of TcdB and their bonding remained stable throughout the simulation studies of 500 ns. Compounds A2129 and A704 can be considered as prospective drug candidates against Clostridioides difficile, however, further wet lab experiments are needed to confirm our study.Communicated by Ramaswamy H. Sarma.

Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative, docking and MD simulation studies.

Abstract: A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability of the obtained candidates to inhibit VEGFR-2 was found to be strong with IC50 values in the range of 76.64-175.50 nM. To investigate the cytotoxicity and safety, all compounds were tested against a panel of four cancer cell lines (A549, Caco2, HepG2 and MDA) as well as two normal cell lines (Vero and WI-38). Interestingly, compound 12 exhibited noticeable cytotoxicity against A549, Caco2 and MDA with IC50 values of 5.40, 0.58 and 0.94 µM, respectively. These results were better and comparable to that of doxorubicin (0.70, 0.82 and 0.90 µM, respectively) with more than three folds higher selectivity index against the Caco2 cell lines. Compound 9 prevented the healing of the cancer cells at a low concentration. Also, the compound's potential to induce programmed cell death in Caco-2 was proved through the significant down regulating of the expression of Bcl2, Bcl-xl and Survivin in addition to the slight upregulation of the TGF-β gene. The cell cycle analysis indicated that compound 9 arrested the Caco-2 cells in the G2/M phase. Interestingly, the molecular docking studies against VEGFR-2 revealed the correct binding of the targeted compounds similar to sorafenib. Furthermore, MD experiments validated the binding of compound 12 with VEGFR-2 over 100 ns, as well as MM-PBSA analysis that confirmed the precise binding with optimum energy. Finally, ADMET analysis showed the general drug-likeness and confirmed the safety of the tested compounds.Communicated by Ramaswamy H. Sarma.

Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil.

Abstract: The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, São Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype.

Potential of plant extracts in targeting SARS-CoV-2 main protease: an in vitro and in silico study.

Abstract: The deaths caused by the covid-19 pandemic have recently decreased due to a worldwide effort in vaccination campaigns. However, even vaccinated people can develop a severe form of the disease that requires ICU admission. As a result, the search for antiviral drugs to treat these severe cases has become a necessity. In this context, natural products are an interesting alternative to synthetic medicines used in drug repositioning, as they have been consumed for a long time through traditional medicine. Many natural compounds found in plant extracts have already been shown to be effective in treating viral and bacterial diseases, making them possible hits to exploit against covid-19. The objective of this work was to evaluate the antiviral activity of different plant extracts available in the library of natural products of the Universidade Estadual de Maringá, by inhibiting the SARS-CoV-2 main protease (Mpro), and by preventing viral infection in a cellular model. As a result, the extract of Cytinus hypocistis, obtained by ultrasound, showed a Mpro inhibition capacity greater than 90%. In the infection model assays using Vero cells, an inhibition of 99.6% was observed, with a selectivity index of 42.7. The in silico molecular docking simulations using the extract compounds against Mpro, suggested Tellimagrandin II as the component of C. hypocistis extract most likely to inhibit the viral enzyme. These results demonstrate the potential of C. hypocistis extract as a promising source of natural compounds with antiviral activity against covid-19.Communicated by Ramaswamy H. Sarma.