The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

Antitumor studies -- part 2: structure-activity relationship study for flavin analogs including investigations on their in vitro antitumor assay and docking simulation into protein tyrosine kinase

Various analogs of flavins, 5-deazaflavins, and flavin-5-oxides were docked into the binding site of protein tyrosine kinase pp60(c-src), and some of them were assayed for their potential antitumor and PKC (protein kinase C) inhibitory activities in vitro. The results considering SAR (structure-activity relationship) revealed that the higher binding affinities obtained include compounds with the structure modifications on the flavin or 5-deazaflavin skeleton, namely, NH(2) or Ph (phenyl-) group at the C-2 position and so on. Computationally designed compounds 4a, 6a, b, 7, 11b, c, 12, 15, and 22c exhibited good docking results suggesting that they are potentially active antitumor agents. These compounds have 1-3 phenyl moieties, which are thought to be responsible for the planar aromatic fitting or electrostatic attraction onto the groove of the binding pocket.     

薯蓣皂苷元衍生物的合成和抗肿瘤活性研究

目的合成薯蓣皂苷元衍生物并研究其体外抗肿瘤活性。方法以薯蓣皂苷元为原料,选择性地合成一系列运用AutoDock4.2对接设计的薯蓣皂苷元衍生物。采用噻唑蓝(MTT)法考察了目标化合物对人恶性黑色素瘤细胞A375、人肺腺癌细胞A549、人肝癌细胞HepG-2以及人慢性髓原白血病细胞K562进行体外抗肿瘤活性试验。结果合成12个新化合物,其结构经1H-NMR和13C-NMR确定,药理实验结果表明,大部分化合物有一定的抗肿瘤活性。结论大部分化合物有良好的抗肿瘤活性而对正常细胞无毒或低毒性。     

Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors

Loperamide is a piperidine analogue, acting as agonist on peripheral opioid receptors, exhibiting affinity and selectivity for the cloned mu human opioid receptor compared with the delta human opioid receptor. Automatic docking studies of loperamide, using AutoDock, on human mu- and delta-opioid receptors is described. Whilst no meaningful difference was detected concerning the docking of the arylpiperidine moiety, mu/delta selectivity could be explained as a different accommodation of the two phenyl groups in two lipophylic pockets of receptors.     

Synthesis,characterization, molecular modelling and biological evaluation of thieno‐pyrimidinone methanesulphonamide thio‐derivatives as non‐steroidal anti‐inflammatory agents

This study reports the synthesis, molecular docking and biological evaluation of eight ( 5 ‐ 8 and 5a ‐ 8a ) newly synthesized thieno‐pyrimidinone methanesulphonamide thio‐derivatives. The synthetic route used to prepare the new isomers thioaryl and thio‐cycloesyl derivatives of the heterocyclic system 6‐phenylthieno[3,2]pyrimidinone was economically and environmentally very advantageous and characterized by the simplicity of procedure, reduction in isolation steps, purification phases, time, costs and waste production. The study in silico for the evaluation of cyclooxygenase (COX)‐1 and COX‐2 selective inhibition was carried out by AutoDock Vina, an open‐source program for doing molecular docking which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. The research in vitro for the biological evaluation was performed by using human cartilage and chondrocytes cultures treated with 10 ng/mL of interleukin‐1beta as inflammation models. The anti‐inflammatory activity of each new compound at the concentration of 10 μmol/L was determined by assaying COX‐2, inducible nitric oxide synthetase (iNOS) and intercellular adhesion molecule 1 (ICAM 1) through Western blot. The examined derivatives showed interesting pharmacological activity, and the compound N‐[2‐[2,4‐difluorophenyl)thio]‐4‐oxo‐6‐phenylthieno[3,2‐d]pyridine‐34H‐yl]methanesulphonamide ( 7 ) was excellent COX‐2 inhibitor. In agreement with the biological data, compound 7 was able to fit into the active site of COX‐2 with highest interaction energy. These results can support the design of novel specific inhibitors of COX‐2 by the comparative modelling of COX‐1 and COX‐2 enzymes with the available pharmacophore.     

Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping

Solution-state nuclear magnetic resonance (NMR) is a versatile tool for the study of binding interactions between small molecules and macromolecular targets. We applied ligand-based NMR techniques to the study of human thymidylate synthase (hTS) using known nanomolar inhibitors and a library of small molecule fragments. Screening by NMR led to the rapid identification of ligand pairs that bind in proximal sites within the cofactor-binding pocket of hTS. Screening hits were used as search criteria within commercially available sources, and a subset of catalog analogs were tested for potency by in vitro assay and binding affinity by quantitative saturation transfer difference (STD)-NMR titration. Two compounds identified by this approach possess low micromolar affinity and potency, as well as excellent binding efficiency against hTS. Relative binding orientations for both leads were modeled using AutoDock, and the most likely bound conformations were validated using experimentally derived STD-NMR binding epitope data. These ligands represent novel starting points for fragment-based drug design of non-canonical TS inhibitors, and their binding epitopes highlight important and previously unexploited interactions with conserved residues in the cofactor-binding site.     

Molecular Modeling and Docking Study to Elucidate Novel Chikungunya Virus nsP2 Protease Inhibitors

Chikungunya is one of the tropical viral infections that severely affect the Asian and African countries. Absence of any suitable drugs or vaccines against Chikungunya virus till date makes it essential to identify and develop novel leads for the same. Recently, nsP2 cysteine protease has been classified as a crucial drug target to combat infections caused by Alphaviruses including Chikungunya virus due to its involvement viral replication. Here in, we investigated the structural aspects of the nsP2 protease through homology modeling based on nsP2 protease from Venezuelan equine encephalitis virus. Further, the ligands were virtually screened based on various pharmacological, ADME/Tox filters and subjected to docking with the modeled Chikungunya nsP2 protease using AutoDock4.2. The interaction profiling of ligand with the protein was carried out using LigPlot⁺. The results demonstrated that the ligand with PubChem Id (CID_5808891) possessed highest binding affinity towards Chikungunya nsP2 protease with a good interaction profile with the active site residues. We hereby propose that these compounds could inhibit the nsP2 protease by binding to its active site. Moreover, they may provide structural scaffold for the design of novel leads with better efficacy and specificity for the nsP2 protease.     

Virtual screening with AutoDock: theory and practice

Importance of the field: Virtual screening is a computer-based technique for identifying promising compounds to bind to a target molecule of known structure. Given the rapidly increasing number of protein and nucleic acid structures, virtual screening continues to grow as an effective method for the discovery of new inhibitors and drug molecules.

Areas covered in this review: We describe virtual screening methods that are available in the AutoDock suite of programs and several of our successes in using AutoDock virtual screening in pharmaceutical lead discovery.

What the reader will gain: A general overview of the challenges of virtual screening is presented, along with the tools available in the AutoDock suite of programs for addressing these challenges.

Take home message: Virtual screening is an effective tool for the discovery of compounds for use as leads in drug discovery, and the free, open source program AutoDock is an effective tool for virtual screening.