Focused Combinatorial Library Design Based on Structural Diversity, Druglikeness and Binding Affinity Score

Abstract

The advent of focused library and virtual screening has reduced the disadvantage of combinatorial chemistry and changed it to a realizable and cost-effective tool in drug discovery. Usually, genetic algorithms (GAs) are used to quickly finding high-scoring molecules by sampling a small subset of the total combinatorial space. Therefore, scoring functions play essential roles in focused library design. Reported here is our initial attempt to establish a new approach for generating a target-focused library using the combination of the scores of structural diversity and binding affinity with our newly improved drug-likeness scoring functions. Meanwhile, a software package, named LD1.0, was developed on the basis of the new approach. One test on a cyclooxygenase (COX)2-focused library successfully reproduced the structures that have been experimentally studied as COX2-selective inhibitors. Another test is on a peroxisome proliferator-activated receptors gamma-focused library design, which not only reproduces the key fragments in the approved (thiazolidinedione) TZD drugs, but also generates some new structures that are more active than the approved drugs or published ligands. Both of the two tests took approximately 15% of the running time of the ordinary molecular docking method. Thus, our new approach is an effective, reliable, and practical way for building up a properly sized focused library with a high hit rate, novel structure, and good ADME/T profile.

Toward understanding the molecular basis for chemical allosteric modulator design

“…In drug discovery, it is desirable to screen a focused chemical library against a drug target, which could result in an improved "hit" rate from the screening [34]. Therefore, the allosteric features of the chemical library are crucial for the screening of allosteric modulators.…”

A QSAR Study on Indole‐Based PPAR‐γ Agonists in Respect to Receptor Binding and Gene Transactivation Data

“…Recently, the population of indole -based derivatives as PPAR-g agonists tends to increase, since the indole core is recognized as a privileged drug-like scaffold [4]. Independently of the chemical class they belong to, typical PPAR-g ligands usually possess an acidic head, a central aromatic moiety and a hetero-aromatic lipophilic tail [5,6].…”

An Approach to Computer Aided Drug Design of some Bioactive Cinnamoyl Hydrazones, In Silico and Docking Studies as Possible COX-2 Selective Inhibitors

“…Mol soft offers software tools and services in lead discovery, modelling, cheminformatics, bioinformatics, and corporate data management; and forms partnerships with biotechnology and pharmaceutical companies. The drug-likeness scores were analyzed by comparing with the earlier reports [25]. Bioactivity score predictions were also done using Mol inspiration online tool.…”