Construction and application of pharmacophore model of human carboxylesterase 2 inhibitors / 中国中药杂志

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.

Ligand- and structure-based pharmacophore modeling, docking study reveals 2-[[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3-b] pyridin-6-yl] amino] ethanol as a potential anticancer agent of CDK9/cyclin T1 kinase

Objective: CDK9/Cyclin T1 kinase is a protein kinase, indirectly involved in the cell cycle progression in the form of transcription elongation, CDK9 specific inhibitors may be a potential alternative treatment not only for cancer but also other life-threatening diseases. Materials and Methods: Ligand-based and structure-based pharmacophore model was developed for discovering of the new anticancer agents. These models used as three-dimensional query for virtual screening against the chemical structure databases such as Maybridge HitFinder, MDPI, and ZINC. Subsequently, the potential hit compound was filtered by the ADMET and docking score. Results: After applying all filtration, 11 hits were found as potential hits based on good docking scores as well as good ADMET properties. Compound 2-[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3-b] pyridin-6-yl] amino] ethanol was found to be most potent among all the potential hits. These hits could be used as an anticancer agent in near future. Conclusions: So many advances in the treatment of death leading diseases have been made over the past few decades, However, looking for the development in this research ligand-based and structure-based pharmacophore modeling was done, hit1 2-[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3 b] pyridin-6 yl] amino] ethanol was found to be more potent and selective. It is understandable that these hits could be as selective and potent anticancer agents of cyclin-dependent kinase complex

The construction of pharmacophore model for(1,3)-β-D-glucan synthase small molecule inhibitors / 药学实践杂志

Objective To perform the ligand-based computer-aided drug design and construct the pharmacophore model of(1,3)-β-D-Glucan Synthase(GS)small molecule inhibitors.Method Six small molecules with diverse structures and good inhibitory activity were selected to construct the training set.The HipHop algorithm in Catalyst pharmacophore generation module was utilized to construct the pharmacophore models.The pharmacophore models were evaluated by constructed Decoy-set 3D database.Results Pharmacophore 02 has a good enrichment factor,sensitivity and specificity parameters.Pharmacoph-ore model validation with Decoyset 3D database proved that the model has good distinguishing capability.Conclusion The pharmacophore model of GS small molecule inhibitors was constructed and tested.It will provide valuable information for de-sign and discovery of novel small molecule GS inhibitors.

Computer Aided Drug Designing

Designing of drugs and their development are a time and resource consuming process. There is an increasing effort to introduce the role of computational approach to chemical and biological space in order to organise the design and development of drugs and their optimisation. The role of Computer Aided Drug Designing (CADD) are nowadays expressed in Nanotechnology, Molecular biology, Biochemistry etc. It is a diverse discipline where various forms of applied and basic researches are interlinked with each other. Computer aided or in Silico drug designing is required to detect hits and leads. Optimise/ alter the absorption, distribution, metabolism, excretion and toxicity profile and prevent safety issues. Some commonly used computational approaches include ligand-based drug design, structure-based drug design, and quantitative structure-activity and quantitative structure-property relationships. In today's world, due to an avid interest of regulatory agencies and, even pharmaceutical companies in advancing drug discovery and development process by computational means, it is expected that its power will grow as technology continues to evolve. The main purpose of this review article is to give a brief glimpse about the role Computer Aided Drug Design has played in modern medical science and the scope it carries in the near future, in the service of designing newer drugs along with lesser expenditure of time and money

Crystal structures, absolute configurations and molecular docking studies of naftopidil enantiomers as-adrenoceptor antagonists

Chiral drug naftopidil (NAF), a specific-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the-AR, but the binding mechanism of these two stereochemical NAF isomers to thereceptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data ofandenantiomers matched satisfactorily the pharmacophore model for-selective antagonists. Based on the constructedhomology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.

Screening and Validation of Active Ingredients in Sini Decoction by Combination Method of Pharmacophore Modeling and Molecular Docking / 中草药·英文版

Objective: To screen the active compounds in Sini Decoction showing the potential to inhibit tumor necrosis factor α (TNFα) to alleviate Doxorubicin (DOX)-induced heart failure. Methods: A chemical database of Sini Decoction was constructed from literature research. The generated pharmacophore models based on TNF-α used to screen active ingredients of Sini Decoction in the database by Discovery Studio 2.5. Molecular docking by Autodock 4.2 was adopted to demonstrate the hit compounds' affinities with TNFα. Furthermore, DOX-induced heart failure model on H9c2 cell line was constructed and cell viability was detected by CCK-8 to validate the therapeutic effect of potential active compounds. Results: The higenamine showed potential cardiovascular protective effect through virtual screening. And the activity was identified in vitro. Conclusion: In this study, we found that higenamine may inhibit TNF-α through virtual docking and validated that higenamine may have the potential of treatment for heart failure in the model of doxorubicin-induced myocardial toxicity to H9c2 cells.

Discovery of potential ATP-sensitive potassium channel openers with potential hypotensive activity from Chinese herbs based on molecular simulation / 中国中药杂志

In this research, a combined method of ligand-based pharmacophore (LBP), structure-based pharmacophore (SBP), and molecular docking was applied for virtual screening potential ATP-sensitive potassium channel (KATP) openers from Chinese herbs. LBP models were generated by 3D-QSAR pharmacophore(hypogen) program, based on the training set composed of 48 KATP agonists. The best LBP model consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic feature, one aromatic ring and five excluded volumes. Besides, the correlation coefficient of training set and test set, N, and CAI value of the model were 0.876 4, 0.705 8, 3.304, and 2.616 respectively. Meanwhile, SBP models were also generated based on a 3D structure of KATP (PMID: PM0079770). The best SBP model consisted of six hydrogen-bond acceptors, eight hydrogen-bond donors, seven hydrophobic features and eighteen excluded volumes. The corresponding N and CAI value were 2.200 and 2.017. Then, the best LBP model and SBP model were applied to identify potential KATP openers from Traditional Chinese Medicine Database(TCMD), respectively. 349 hits were obtained after analyzed by drug-likeness rules. Moreover, 12 compounds with high docking scores were reserved after molecular docking evaluation. Interestingly, part of the results had been verified as hypotensive active ingredients by literatures. Therefore, this study uncovers a specific target effect contained in TCMD, and provides candidates for new KATP openers' research.

Construction and application of 3D-pharmacophore model of glucokinase agonists / 中国药科大学学报

@#Glucokinase(GK), which plays a pivotal role in maintaining glucose equilibrium in the human body, emerged as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of glucokinase agonist inhibitors have been generated with a training set of 25 glucokinase agonists(EC50 values from 2 to 78 000 nmol/L)using Discovery studio 2. 5. The best hypothesis contained three hydrogen bond acceptors, one hydrophobic center, and three excluded volumes with a correlation coefficient of 0. 955, cost difference of 60. 5, RMSD of 0. 714. This model was validated by test set, Fischer randomization test and decoy set methods. Pharmacophore model was also utilized as a three dimentional query to screen in-house andrographolide derivative database. New potential GK agonist was obtained therewith, and the hit compound is capable for further screening assay studies. Preliminary biological evaluation suggests that this new pharmacophore model fuctions superiorly in virtual screening.

Construction of 3D pharmacophore model of vascular endothelial growth factor receptor 2 inhibitors / 第二军医大学学报

Objective To construct the three dimensional pharmacophore models of inhibitors of vascular endothelial growth factor receptor 2 (VEGFR-2), so as to provide a theoretical model for designing novel VEGFR-2 inhibitors. Methods The model was derived from 30 reported VEGFR-2 inhibitors (21 molecules as training set and the rest as testing set) with structural variety and resembling binding mode, whose IC50 values spanned 5 magnitudes by using Catalyst Software in Discovery Studio 2. 5 Package. Results The best model consists of one hydrogen bond receptor, two hydrophobic cores, one aromatic plane and 4 excluded volumes. The predictive relativity (i?) was 0. 89. Conclusion Cross-validation results indicate that the constructed model has satisfactory predictivity and can be used to screen molecule databases for searching novel lead compounds which can inhibit VEGFR-2.

Design and Synthesis of New γ-Secretase Inhibitors / 华中科技大学学报(医学版)

Objective By virtual screening in MDL,to search for a novel γ-secretase inhibitor.Methods A series of compounds were designed,synthesized,and evaluated based on pharmacophore model of γ-secretase inhibitors by virtual screening in MDL.Results The drug-likeness analytic data synthesized indicated that target compounds had drug-likeness.Each svnthesized compound was checked by IR spectroscopy,~1H and ~(13)C-NMR spectroscopy.Conclusion The designed compounds had better activity by model prediction.And the optimal compound showed a significant estimated activity value of 0.025 nmol/L and can be used as a lead for further drug development.