Showing papers on "Pharmacophore published in 2019"
TL;DR: Six potential inhibitory molecules have been selected by analyzing the binding interaction and Ligand-Pharmacophore mapping with the validated pharmacophore model and MD simulation of these three molecules proved that the ligand binding into the protein-DNA cleavage complex is stable and theprotein-ligands conformation remains unchanged.
Abstract: Camptothecin (CPT), a natural product and its synthetic derivatives exert potent anticancer activity by selectively targeting DNA Topoisomerase I (Top1) enzyme. CPT and its clinically approved derivatives are used as Top1 poisons for cancer therapy suffer from many limitations related to stability and toxicity. In order to envisage structurally diverse novel chemical entity as Top1 poison with better efficacy, Ligand-based-pharmacophore model was developed using 3D QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery studio 4.1 clients. The chemical features of 29 CPT derivatives were taken as the training set. The selected pharmacophore model Hypo1 was further validated by 33 test set molecules and used as a query model for further screening of 1,087,724 drug-like molecules from ZINC databases. These molecules were subjected to several assessments such as Lipinski rule of 5, SMART filtration and activity filtration. The molecule obtained after filtration was further scrutinized by molecular docking analysis on the active site of Top1 crystal structure (PDB ID: 1T8I). Six potential inhibitory molecules have been selected by analyzing the binding interaction and Ligand-Pharmacophore mapping with the validated pharmacophore model. Toxicity assessment TOPKAT program provided three potential inhibitory 'hit molecules' ZINC68997780, ZINC15018994 and ZINC38550809. MD simulation of these three molecules proved that the ligand binding into the protein-DNA cleavage complex is stable and the protein-ligands conformation remains unchanged. These three hit molecules can be utilized for designing future class of potential topoisomerase I inhibitor.
95 citations
TL;DR: In this paper, a structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site.
74 citations
TL;DR: An efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites, which provides a new method of identifying ligand sites, assessing tractability and discovering new leads.
Abstract: Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource-intensive screening of large libraries of lead-like or fragment molecules. Here, we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence...
53 citations
TL;DR: The molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau, which showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion and admetSAR toxicity tests.
Abstract: The purpose of our study is to identify phosphorylated tau (p-tau) inhibitors. P-tau has recently received great interest as a potential drug target in Alzheimer’s disease (AD). The continuous failure of Aβ-targeted therapeutics recommends an alternative drug target to treat AD. There is increasing evidence and growing awareness of tau, which plays a central role in AD pathophysiology, including tangles formation, abnormal activation of phosphatases/kinases, leading p-tau aggregation in AD neurons. In the present study, we performed computational pharmacophore models, molecular docking, and simulation studies for p-tau in order to identify hyperphosphorylated sites. We found multiple serine sites that altered the R1/R2 repeats flanking sequences in the tau protein, affecting the microtubule binding ability of tau. The ligand molecules exhibited the p-O ester scaffolds with inhibitory and/or blocking actions against serine residues of p-tau. Our molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau. These five ligands showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion (ADME) and admetSAR toxicity tests. The p-tau pharmacophore based drug discovery models provide the comprehensive and rapid drug interventions in AD, and tauopathies are expected to be the prospective future therapeutic approach in AD.
52 citations
TL;DR: Additional hit finding, evaluation, and structure-based scaffold morphing led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2.SHP2, and demonstrated the structural diversity permitted by the tunnel pharmacophore.
Abstract: SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for furth...
51 citations
TL;DR: In this paper, a series of novel PI3K and HDAC dual inhibitors were discovered in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3k pharmacophore through an appropriate linker.
Abstract: Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
48 citations
TL;DR: New series of phthalimide-sulfonylurea hybrids prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug showed promising estimated activities.
45 citations
TL;DR: A six-point e-pharmacophore model was built and used for virtual screening of a focussed library of 5900 compounds, which was downloaded from ZINC 15 database and results suggested that identified hits have drug like physico-chemical properties.
40 citations
TL;DR: It is concluded that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
Abstract: Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules—proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Ne of His in a manner that preserves the Pt–As bond. We find that AP-1 readily enters cells and bind...
38 citations
TL;DR: This new class of B NTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-Tubercular drugs.
Abstract: Background Benzothiazole derivatives are known for anti-TB properties Based on the known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1-7 and BNTZ 8-13) Objective The study aims to carry out the development of benzothiazole based anti-TB compounds Methods Title compounds are synthesized by microwave method and purified by column chromatography Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method Results It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 µg/mL and 11 µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M tuberculosis, respectively One of the selected BNTZ derivatives BNTZ 13 was used for single crystal X-ray studies Conclusion To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2'-oxidase The interaction is derived by forming favorable hydrogen bonds and stacking interactions This new class of BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs
37 citations
11 Jul 2019
TL;DR: ADME results indicated that compounds 16, N9 and W20 have significant results within the close agreement of the Lipinski’s rule of five and Qikprop rule within the range and these compounds may be taken as lead molecules for the discovery of new anticancer agents.
Abstract: Benzimidazole is a valuable pharmacophore in the field of medicinal chemistry and exhibit wide spectrum of biological activity. Molecular docking technique is routinely used in modern drug discovery for understanding the drug-receptor interaction. The selected data set of synthesized benzimidazole compounds was evaluated for its in vitro anticancer activity against cancer cell lines (HCT116 and MCF7) by sulforhodamine B (SRB) assay. Further, molecular docking study of data set was carried out by Schrodinger-Maestro v11.5 using CDK-8 (PDB code: 5FGK) and ER-alpha (PDB code: 3ERT) as possible target for anticancer activity. Molecular docking results demonstrated that compounds 12, 16, N9, W20 and Z24 displayed good docking score with better interaction within crucial amino acids and corelate to their anticancer results. ADME results indicated that compounds 16, N9 and W20 have significant results within the close agreement of the Lipinski’s rule of five and Qikprop rule within the range and these compounds may be taken as lead molecules for the discovery of new anticancer agents.
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: Findings suggested that PBS-8 is a promising candidate that could be bedeveloped as a potential antiepileptic.
Abstract: Pyrrolone-fused benzosuberene (PBS) compounds were semi-synthesized from α,β,γ-Himachalenes extracted from the essential oil of Cedrus deodara following amino-vinyl-bromide substituted benzosuberenes as intermediates. These PBSs compounds classified as an attractive source of therapeutics. The α-isoform of PI3K which is a pivotal modulator of PI3K/AKT/mTOR signaling pathway, responsible for neurological disorders like epilepsy, found as a potential target molecule against these 17 semi-synthesized PBS compounds using in silico ligand-based pharmacophore mapping and target screening. The compounds screened using binding affinities, ADMET properties, and toxicity that were accessed by in silico docking simulations and pharmacokinetics profiling. Ultimately two compounds viz., PBS-8 and PBS-9 were selected for further in vivo evaluation using a zebrafish (Danio rerio) model of pentylenetetrazol (PTZ)-induced clonic convulsions. Additionally, gene expression studies performed for the genes of the PI3K/AKT/mTOR pathway which further validated our results. In conclusion, these findings suggested that PBS-8 is a promising candidate that could bedeveloped as a potential antiepileptic.
TL;DR: It is shown that 2-aryl-4H-chromene core retains pharmacophore properties while being readily available synthetically as analogs of naturally occurring flavonoids with prominent α-glucosidase inhibitory properties.
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: A comparative study involving a set of more than 25,000 structures from the authors' internal database that had been screened for σ1R affinity provides a sound basis for the generation and validation of predictive models to design new molecules.
Abstract: The recent publication of the σ1R crystal structure is an important cornerstone for the derivation of more accurate activity prediction models. We report here a comparative study involving a set of more than 25,000 structures from our internal database that had been screened for σ1R affinity. Using the recently published crystal structure, 5HK1, two new pharmacophore models were generated. The first one, 5HK1-Ph.A, was obtained by an algorithm that identifies the most important receptor-ligand interactions including volume restrictions enforced by the atomic structure of the recognition site. The second, 5HK1-Ph.B, resulted from a manual edition of the first one by the fusion of two hydrophobic (HYD) features. Finally, we also docked the database using a high throughput docking technique and scored the resulting poses with seven different scoring functions. Statistical performance measures were obtained for the two models, comparing them with previously published σ1R pharmacophores (Hit Rate, sensitivity, specificity, and Receiver Operator Characteristic) and 5HK1-Ph.B emerged as the best one in discriminating between active and inactive compounds, with a ROC-AUC value above 0.8 and enrichment values above 3 at different fractions of screened samples. 5HK1-Ph.B also showed better results than the direct docking, which may be due to the rigidity of the crystal structure in the docking process (i.e., feature tolerances in the pharmacophore model). Additionally, the impact of the HYD interactions and the penalty for desolvating ligands with polar atoms may be not adequately captured by scoring functions, whereas HYD groups filling up such regions of the binding site are entailed in the pharmacophore model. Altogether, using annotated data from a large and diverse compound collection together with crystal structure information provides a sound basis for the generation and validation of predictive models to design new molecules.
TL;DR: Results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway.
Abstract: 3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64–7.73 μg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.
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: A potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore and a lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice.
Abstract: Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.
TL;DR: Among all compounds screened for their antitumor activity, compounds 2f and 2p were found to be the most active and the most obvious changes in the morphology of the treated cells could be observed.
TL;DR: After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.
Abstract: We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.
TL;DR: The new selective TNFα, TNFR1 and TNF–TNFR1 complex inhibitors can serve as anti-inflammatory agents and are promising candidates for further research.
Abstract: Tumor necrosis factor α (TNFα) is a multifunctional cytokine with a potent pro-inflammatory effect. It is a validated therapeutic target molecule for several disorders related to autoimmunity and inflammation. TNFα–TNF receptor-1 (TNFR1) signaling contributes to the pathological processes of these disorders. The current study is focused on finding novel small molecules that can directly bind to TNFα and/or TNFR1, preventing the interaction between TNFα or TNFR1, and regulating downstream signaling pathways. Cheminformatics pipeline (pharmacophore modeling, virtual screening, molecular docking and in silico ADMET analysis) was used to screen for novel TNFα and TNFR1 inhibitors in the Zinc database. The pharmacophore-based models were generated to screen for the best drug like compounds in the Zinc database. The 39, 37 and 45 best hit molecules were mapped with the core pharmacophore features of TNFα, TNFR1, and the TNFα–TNFR1 complex respectively. They were further evaluated by molecular docking, protein–ligand interactions and in silico ADMET studies. The molecular docking analysis revealed the binding energies of TNFα, TNFR1 and the TNFα–TNFR1 complex, the basis of which was used to select the top five best binding energy compounds. Furthermore, in silico ADMET studies clearly revealed that all 15 compounds (ZINC09609430, ZINC49467549, ZINC13113075, ZINC39907639, ZINC25251930, ZINC02968981, ZINC09544246, ZINC58047088, ZINC72021182, ZINC08704414, ZINC05462670, ZINC35681945, ZINC23553920, ZINC05328058, and ZINC17206695) satisfied the Lipinski rule of five and had no toxicity. The new selective TNFα, TNFR1 and TNFα–TNFR1 complex inhibitors can serve as anti-inflammatory agents and are promising candidates for further research.
TL;DR: Findings are found that the screened four natural products could serve as the lead compounds for designing the new dual MMP-2/HDAC-6 inhibitors having higher biological activities by carrying out structural modifications and optimizations in the future studies.
Abstract: The dual-target inhibitors tend to improve the response rate in treating tumors, comparing with the single-target inhibitors. Matrix metalloproteinase-2 (MMP-2) and histone deacetylase-6 (HDAC-6) a...
TL;DR: The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities byStructural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.
Abstract: Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.
01 Jan 2019
TL;DR: This chapter aims to provide a short overview of the pharmacophore concept and its applications in modern computer-aided drug design and provides a description of the most common nonbonded interaction types and their representation as pharmacophoric features.
Abstract: Pharmacophore-based techniques currently are an integral part of many computer-aided drug design workflows and have been successfully and extensively applied for tasks such as virtual screening, de novo design, and lead optimization. Pharmacophore models can be derived both in a receptor-based and in a ligand-based manner, and provide an abstract description of essential non-bonded interactions that typically occur between small-molecule ligands and macromolecular targets. Due to their simplistic and abstract nature, pharmacophores are both perfectly suited for efficient computer processing and easy to comprehend by life and physical scientists. As a consequence, they have also proven to be a valuable tool for communicating between computational and medicinal chemists.This chapter aims to provide a short overview of the pharmacophore concept and its applications in modern computer-aided drug design. The chapter is divided into three distinct parts. The first section contains a brief introduction to the pharmacophore concept. The second section provides a description of the most common nonbonded interaction types and their representation as pharmacophoric features. Furthermore, it gives an overview of the various methods for pharmacophore generation and important pharmacophore-based techniques in drug design. This part concludes with examples for recent pharmacophore concept-related research and development. The last section is dedicated to a review of research in the field of natural product chemistry as carried out by employing pharmacophore-based drug design methods.
TL;DR: It was found that 2'-cyanobiphenyl serves as the pharmacophore of AMPK-activating activity, which also increases with the expansion of the external hydrogenated cycle, and render biphenyl derivatives of fused benzimidazoles as a valuable starting point for the development of AM PK activators with multi-target antidiabetic activity.
TL;DR: In vitro evaluation showed that in vitro evaluation of a series of compounds with amide-pyridine scaffolds designed and synthesized to treat the increasing incidence of drug-resistant fungal infections showed that these compounds have a certain degree of antifungal activity.
01 Jun 2019
TL;DR: The ligand library reporting anticancer activities was taken from literature containing forty-two 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives and was thoroughly investigated against cancer target using docking protocol to develop the Atom based- and Field based-3D QSAR models.
Abstract: The ligand library reporting anticancer activities was taken from literature containing forty-two 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives and was thoroughly investigated against cancer target (pdb id-5U6B) using docking protocol. In order to design future analogues, we carried out our research to develop the Atom based- and Field based-3D QSAR (Quantitative structure–activity relationship models) models. PHASE was employed for the common pharmacophore generation and 3D-QSAR studies. The protein target (pdb id-5U6B) was selected and docking was used in order to check better binding modes between target and ligands. The crystal structure of Axl kinase domain in complex with a macrocyclic inhibitor complex (pdb id-5U6B) had a resolution of 2.84 A. The free energy was calculated by using PRIME-Molecular mechanics with generalized Born and surface area solvation (MM/GBSA). The molecular properties and ADME parameter were calculated using Qikprop utility. Out of 12 developed pharmacophore hypothesis using the PHASE module, a six point AAHRRR_1 hypothesis found best with good scoring parameters involving the two acceptor features, one hydrophobic feature and three ring features. For the atom based-3D QSAR model, a good cross-validation correlation coefficient i.e. Q2 value as 0.5715 for test set and R2 (a correlation coefficient) as 0.8704 for training set molecules. In case of field based QSAR, a cross-validation correlation coefficient (Q2) for test set as 0.5697 and R2 (a correlation coefficient) as 0.817 for training set molecules. Both the models show good statistical significance for future designing. The compound 9L observed as best docked for target 5U6B having docking score of −4.085 kcal/mol and PRIME MM/GBSA (Prime/Molecular Mechanics Generalized Born Surface Area) dg bind energy as-63.302 kcal/mol. The values for rule of five for all dataset compounds were found within range. Percentage human oral absorption values were also >80% except few compounds. Finally, our current study will helpful for researchers in order to develop new 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives as more potent anticancer agents.
TL;DR: The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors.
TL;DR: The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was demonstrated and the order of administration of the inhibitor and topotican on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitors is the mosteffective.
Abstract: Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective.