Application Of Molecular Modelling Technologies In Drug Discovery

The discovery of lead compounds is a critical step in developing new drugs.With the rapid development of computational technique and hardware,the methods of computer-aided drug design(CADD)have become indispensable tools in the area of target discovery and validation,high-throughput screening,drug optimization,and prediction of drug activity,pharmacokinetics and toxicity.Compared with traditional experimental methods,the in silico methods are cheaper and time-saving,which significantly improve the efficiency of drug discovery.Based on molecular modelling techniques,structure-based virtual screening was performed to search for type-? inhibitors of TIE-2,which leads to the discovery of several nanomolar inhibitors.In conventional virtual screening campaign,clustering analysis can be performed based on the top ranked compounds to maximize the molecular diversity of the candidates.But this practice may have a pronounced influence on the overall hit rates.So,we further assessed the influence of different number of clustering compounds on the overall hit rates based on the same chemical library(ChemBridge),and two groups of VS candidates obtained from different clustering strategies were then experimentally evaluated.Our results demonstrate that the hit rates can be improved when stricter drug-likeness criteria are used,and meanwhile,the molecular diversity of the compounds still maintains.Molecular modelling was also used to design and optimize small-molecule inhibitors.We rationally designed a novel kind of "bridge" inhibitors of ALK,which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK.The novel type-?1/2 inhibitors display excellent anti-proliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs,crizotinib and ceritinib.Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation,enabling persistent sensitivity to different genetic mutations in ALK.In addition,a novel kind of hexacyclic CPT derivatives was first identified and synthesized by analysis of a virtual chemical library and cytotoxicity screening in vitro.These compounds are very promising and exhibit favorable biological properties,including improved solubility,reduced toxicity and enhanced efficacy.Two compounds exhibited remarkable anticancer and anti-inflammation efficacies in in vivo models.