Showing papers in "Journal of Biomolecular Structure & Dynamics in 2019"
TL;DR: A structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors, finding safe and better hits that can be exploited in drug design and development for associated diseases.
Abstract: Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inh...
104 citations
TL;DR: The results of fluorescence resonance energy transfer theory indicated that different sizes of silver nanoparticles could change the binding distance between curcumin and lysozyme, and it was concluded that the limited mobility around the Trp residues decreased in the presence ofsilver nanoparticles with bigger size.
Abstract: This article describes, for the first time, the effect of three different sizes of silver nanoparticles on the binding of curcumin to lysozyme as examined by spectroscopic and zeta potential techni...
91 citations
TL;DR: Experimental results proved that the intercalative binding between PA and ct DNA as well as the (H1-ct DNA) complex as binary and ternary systems must be predominant.
Abstract: DNA is the primary target of many anticancer drugs involved in important intercellular processes, especially in transcriptional regulation, and histone is known to inhibit gene expression. Small mo...
88 citations
TL;DR: The binding kinetics and affinity of LMF to HSA in the absence and presence of the amino acids were studies using stopped-flow circular dichroism and ITC techniques respectively that revealed that the bindig affinity and binding rate of the LMF-HSA interaction decreased in the presence of histidine, methionine and cysteine.
Abstract: The present study was designed to investigate the influence of two indispensable and two dispensable amino acids, including methionine, histidine, cysteine and proline, on the binding interaction between human serum albumin (HSA) and an antibiotic agent lomefloxacin (LMF). The fluorescence quenching experiments showed that the intrinsic emission of HSA was considerably quenched following binding to LMF in all the systems. Furthermore, in all the interactions the maximum wavelength of HSA was slightly decreased. The spectral changes observed in the binding systems we e all attributed to the alteration of the micro-environment around the tryptophan and tyrosine residues of HSA. The Kb values o HSA-LMF complex in the absence and presence of histidine, methionine, cysteine and proline have been obtained 6.02 × 105, 4.83 × 105, 5.05 × 105, 4.94 × 105 and 6.20 × 105 M-1 respectively. The various kind of Kb values showed the different interaction behavior between HSA and LMF in the absence and presence of amino acids mentioned. The data gathered by isothermal titration calorimetry (ITC) studies revealed that although all the binding interactions were exothermic, the amount of the heat exchanged during the HSA-LMF interaction increased in the presence of the amino acids especially cysteine. In the present study, the binding kinetics and affinity of LMF to HSA in the absence and presence of the amino acids were studies using stopped-flow circular dichroism and ITC techniques respectively. The results of these two techniques revealed that the bindig affinity and binding rate of the LMF-HSA interaction decreased in the presence of histidine, methionine and cysteine. In the presence of proline, the binding process of LMF-HSA was sped up and the affinity of LMF to HSA slightly increased. All the experimental results were then supported by the data collected from molecular modeling studies using density functional theory. Communicated by Ramaswamy H. Sarma.
80 citations
TL;DR: The designed vaccine is suggested as a novel construct, capable to elicit efficient humoral and cellular immunities, which are crucial for protection against S. pneumoniae.
Abstract: Streptococcus pneumoniae is a leading cause of some diseases such as pneumonia, sepsis, and meningitis mostly in children less than 5 years of age. Presently, two types of pneumococcal vaccine are ...
74 citations
TL;DR: The goal of this work is to discover novel and diverse lead compounds that act as inhibitors of α-glucosidase such as small peptides by performing a computer aided virtual screening and to find novel scaffolds for further development.
Abstract: Human α-glucosidase is an enzyme involved in the catalytic cleavage of the glucoside bond and involved in numerous functionalities of the organism, as well as in the insurgence of diabetes mellitus 2 and obesity. Thus, developing chemicals that inhibit this enzyme is a promising approach for the treatment of several pathologies. Small peptides such as di- and tri-peptides may be in natural organism as well as in the GI tract in high concentration, coming from the digestive process of meat, wheat and milk proteins. In this work, we reported the first tentative hierarchical structure-based virtual screening of peptides for human α-glucosidase. The goal of this work is to discover novel and diverse lead compounds that my act as inhibitors of α-glucosidase such as small peptides by performing a computer aided virtual screening and to find novel scaffolds for further development. Thus, in order to select novel candidates with original structure we performed molecular dynamics (MD) simulations among the 12 top-ranked peptides taking as comparison the MD simulations performed on crystallographic inhibitor acarbose. The compounds with the lower RMSD variability during the MD, were reserved for in vitro biological assay. The selected 4 promising structures were prepared on solid phase peptide synthesis and used for the inhibitory assay, among them compound 2 showed good inhibitory activity, which validated our method as an original strategy to discover novel peptide inhibitors. Moreover, pharmacokinetic profile predictions of these 4 peptides were also carried out with binary QSAR models using MetaCore/MetaDrug applications.
73 citations
TL;DR: The interaction of Pyrogallol with human serum albumin (HSA) was investigated by UV, fluorescence, Circular dichroism, and molecular docking methods and indicated that PG induced conformational changes in the structure of HSA.
Abstract: In the present study, the interaction of Pyrogallol (PG) with human serum albumin (HSA) was investigated by UV, fluorescence, Circular dichroism (CD), and molecular docking methods. The results of ...
68 citations
TL;DR: Docking results are indicating that ligands are binding to the hydrophobic cavity of the kinase domain of CAMKIV and forming a significant number of non-covalent interactions.
Abstract: Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is associated with many diseases including cancer and neurodegenerative disorders and thus being considered as a potential drug target. Here,...
57 citations
TL;DR: Using the structural and biological activity information of ligands for five important and mostly studied vital targets that are believed to be effective against AD, five classification models using linear discriminant analysis (LDA) technique are developed.
Abstract: Alzheimer’s disease (AD) is a multi-factorial disease, which can be simply outlined as an irreversible and progressive neurodegenerative disorder with an unclear root cause. It is a major cause of ...
56 citations
TL;DR: The compound VS5-e exhibits excellent antimicrobial activities and also shows more chemical reactivity and less toxicity which were confirmed by smaller HOMO–LUMO gap, lesser chemical hardness, higher global softness and lesser electrophilicity index.
Abstract: Schiff bases containing benzothiazole unit are synthesized and characterized by 1H NMR, 13C NMR, LC–MS, UV–visible and fluorescence spectroscopy methods. Synthesized compounds were evaluated for in...
54 citations
TL;DR: The molecular docking and ADMET properties of these compounds with a novel anticancer (HER2) and anti-inflammatory targets revealed that two molecules were capable of inhibiting both the targets, and could be used as multi target inhibitors.
Abstract: Natural products acquire massive structural and chemical diversity, which cannot be coordinated by any synthetic libraries for small molecules and they are continuing to inspire novel discoveries in health sciences. We have performed the computational calculations for geometry optimization and prediction of electronic and structural properties of some plant phenolic compounds through Gaussian 09 program. Energies of molecular orbitals were computed, to mimic out the stabilities arising from charge delocalization and intramolecular interactions. This process indicated the eventual charge transfer within the molecules. The molecular docking and ADMET properties of these compounds with a novel anticancer (HER2) and anti-inflammatory (COX-2) targets revealed that two molecules were capable of inhibiting both the targets, and could be used as multi target inhibitors. Furthermore, molecular dynamics simulation studies were performed to elucidate the binding mechanism and the comparison of inhibitor's binding mode with diverse biological activities as anticancer and anti-inflammatory agents. A high-quality association was reported among quantum chemical, ADMET, docking, dynamics and MMGBSA results. Communicated By Ramaswamy H. Sarma.
TL;DR: A deeper insight is provided into the binding mechanism of simvastatin and CA to ILK, which further opens a promising channel for their implications in cancer therapy.
Abstract: Integrin linked kinase (ILK) is a Ser/Thr kinase, which regulates various integrin mediated signaling pathways, and is involved in cell adhesion, migration and differentiation. Alteration i...
TL;DR: New tailored Cu( II) & Zn(II) metal-based antitumor drug entities were synthesized from substituted benzothiazole o‒vanillin Schiff base ligands and all the Lipinski’s rules were found to be obeyed.
Abstract: New tailored Cu(II) & Zn(II) metal-based antitumor drug entities were synthesized from substituted benzothiazole o‒vanillin Schiff base ligands. The complexes were thoroughly characterized by eleme...
TL;DR: Few best fit molecules of natural origin against identified targets which may give new drugs to combat HIV infection after wet lab validation are identified.
Abstract: AIDS is one of the multifaceted diseases and this underlying complexity hampers its complete cure. The toxicity of existing drugs and emergence of multidrug-resistant virus makes the treatment worse. Development of effective, safe and low-cost anti-HIV drugs is among the top global priority. Exploration of natural resources may give ray of hope to develop new anti-HIV leads. Among the various therapeutic targets for HIV treatment, reverse transcriptase, protease, integrase, GP120, and ribonuclease are the prime focus. In the present study, we predicted potential plant-derived natural molecules for HIV treatment using computational approach, i.e. molecular docking, quantitative structure activity relationship (QSAR), and ADMET studies. Receptor-ligand binding studies were performed using three different software for precise prediction - Discovery studio 4.0, Schrodinger and Molegrow virtual docker. Docking scores revealed that Mulberrosides, Anolignans, Curcumin and Chebulic acid are promising candidates that bind with multi targets of HIV, while Neo-andrographolide, Nimbolide and Punigluconin were target-specific candidates. Subsequently, QSAR was performed using biologically proved compounds which predicted the biological activity of compounds. We identified Anolignans, Curcumin, Mulberrosides, Chebulic acid and Neo-andrographolide as potential natural molecules for HIV treatment from results of molecular docking and 3D-QSAR. In silico ADMET studies showed drug-likeness of these lead molecules. Structure similarities of identified lead molecules were compared with identified marketed drugs by superimposing both the molecules. Using in silico studies, we have identified few best fit molecules of natural origin against identified targets which may give new drugs to combat HIV infection after wet lab validation.
TL;DR: Other naphthofuran derivatives are explored for their potential to inhibit BACE-1 and GSK-3β through docking, molecular dynamics, binding energy, and energy decomposition per residue.
Abstract: BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer’s disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (tr...
TL;DR: The collaborative results of spectroscopic studies indicated that the microenvironment and the conformation of HSA and BSA were significantly perturbed upon interaction with complex [C36H50N8O6Cu].
Abstract: The interaction studies of CuII nalidixic acid–DACH chemotherapeutic drug entity, [C36H50N8O6Cu] with serum albumin proteins, viz., human serum albumin (HSA) and bovine serum albumin (BSA) employin...
TL;DR: Evaluated synergy potential and understanding the drug resistance reversal mechanism of chanoclavine isolated from Ipomoea muricata against the multi-drug-resistant clinical isolate of Escherichia coli (MDREC), and it is hypothesized that chanOClavine might be inhibiting the efflux of tetracycline from MDREC and thus enabling the more availability of tTracecline inside the cell for its action.
Abstract: The emergence of multi drug resistance (MDR) in Gram-negative bacteria (GNB) and lack of novel classes of antibacterial agents have raised an immediate need to identify antibacterial agents, which ...
TL;DR: The study suggests that the aforementioned lead candidates and targets can be used for structure-based drug screening towards MDR A. baumannii.
Abstract: Acinetobacter baumannii, an opportunistic pathogen, has become multi-drug resistant (MDR) to major classes of antibacterial and poses grave threat to public health. The current study focused to scr...
TL;DR: The results lend insight into distinctive structural effects of germline PTEN mutations associated withPTEN-ASD vs. those associated with PTEN-cancer, potentially aiding in identification of the shared and separate molecular features that contribute to autism or cancer, thus, providing a deeper understanding of genotype–phenotype relationships for germlinePTEN mutations.
Abstract: Individuals with germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN), irrespective of clinical presentation, are diagnosed with PTEN hamartoma tumor syndrome (PHTS...
TL;DR: It is found that the presence or absence of K+ not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings, which could therefore be useful for further structure-based drug design studies addressing newHDAC1 inhibitors.
Abstract: Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K+) in both sites (HDAC1k), a second with K+ only at site 1 (HDAC1ks1), a third with K+ only at site 2 (HDAC1ks2) and a fourth with no K+ (HDAC1wk). We found that the presence or absence of K+ not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors.
TL;DR: Herring sperm DNA was selected as a model DNA for evaluating the binding interaction of sunitinib with DNA and is expected to gain the characteristic binding information regarding the binding affinity, stoichiometry, binding forces, binding mode, and among others by employing UV–Vis spectroscopy, fluorescence spectroscopic, circular dichroism (CD) as well as viscosity measurement.
Abstract: Sunitinib (Figure 1) is a multi-targeted receptor tyrosine kinase (RTK) inhibitor (Lee & Motzer, 2015), which has been widely used to treat renal cell carcinoma (RCC) (Wentink et al., in press), pa...
TL;DR: The study illustrates that the combined pharmacophore approach is advantageous to identify diverse hits which have better binding affinity to the active site of the enzyme for all possible bioactive conformations.
Abstract: Matrix metalloproteinase-9 (MMP-9) is a significant target for the development of drugs for the treatment of arthritis, CNS disorders, and cancer metastasis. The structure-based and ligand-based me...
TL;DR: Hydrogen bonding with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure and was reported as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.
Abstract: In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of −51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to ...
TL;DR: To understand the effect of urea on the nature of the interaction between TG and f-GONS, molecular dynamics simulation was employed and the results indicated that in the presence of Urea the adsorption process gets affected and leads to instability of system, while the affinity of the TG for adsorbed onto GO surface is increased in pure water.
Abstract: In this study, the interaction thioguanine (TG) anticancer drug with the functionalized graphene oxide (GO) nanosheet surface is theoretically studied in both gas phase and separately in physiologi
TL;DR: The analysis of atomistic molecular dynamics simulations at two different temperatures indicates that there are distinct structural differences in the unfolding pathway between the two domains and RRM1 unfolds faster than RRM2 in accordance with the lower thermal stability found experimentally.
Abstract: TAR DNA-binding protein 43 (TDP-43) inclusions have been found in Amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases. Many studies suggest the involvement of RNA recog...
TL;DR: The observed percentage growth inhibition against A549, HepG2, MCF-7, and NHDF cell lines suggest that complex (1) has exhibited superior anticancer potency than others, and may contribute as potential anticancer agent due to its unique interaction mode with DNA.
Abstract: A novel series of bioactive water soluble mixed ligand complexes (1–5) [MII(L)(phen)AcO]. nH2O {where M = Cu (1) n = 2; Co (2), Mn (3), Ni (4), n = 4 and Zn (5) n = 2} were synthesized from 2-(2-Mo...
TL;DR: Combined pharmacophore mapping and molecular docking were used to identify the potential plant-based hits against the various receptors of dengue virus which can be further validated by bioactivity-based experiments.
Abstract: Dengue is a fast spreading mosquito borne viral disease that poses a serious threat to human health. Lack of therapeutic drugs and vaccines signify that more resources need to be explored. Accumula...
TL;DR: The proposed de novo designed molecules can be considered as promising antibacterial chemical agents subject to experimental validation, in vitro.
Abstract: The rapidly increasing rate of antibiotic resistance is of great concern. Approximately two million deaths result annually from bacterial infections worldwide. Therefore, there is a paramount requi...
TL;DR: Multi-conformation dynamic pharmacophore models from the donepezyl-binding pocket based on highly populated structures chosen from molecular dynamics simulations were used for screening compounds that can properly bind acetylcholinesterase.
Abstract: Acetylcholinesterase is a critical enzyme that regulates neurotransmission by catalyzing the breakdown of neurotransmitter acetylcholine in synapses of the nervous system. It is an important target...
TL;DR: Experimental results showed that GEF can bind to DNA via a groove binding mode, and with the addition of GEF to DNA, the zeta potential decreased gradually, indicating that the hydrophobic interaction between the GEF and the bases of DNA is the major factor.
Abstract: This study was carried out to evaluate the binding interaction of gefitinib (GEF) with human serum albumin (HSA) and calf thymus DNA (ct-DNA) using fluorescence, UV–Visible, zeta potential measurem...