Affiliation:
1. Bioinformatics Division, ICMR—National Institute of Cancer Prevention and Research Noida Uttar Pradesh India
2. Amity Institute of Biotechnology Amity University Uttar Pradesh Noida Uttar Pradesh India
3. Schrödinger India Private Limited Bengaluru Karnataka India
Abstract
AbstractVirtual screening (VS) is a routine method to evaluate chemical libraries for lead identification. Therefore, the selection of appropriate protein structures for VS is an essential prerequisite to identify true actives during docking. But the presence of several crystal structures of the same protein makes it difficult to select one or few structures rationally for screening. Therefore, a computational prioritization protocol has been developed for shortlisting crystal structures that identify true active molecules with better efficiency. As identification of small‐molecule inhibitors is an important clinical requirement for the T790M/L858R (TMLR) EGFR mutant, it has been selected as a case study. The approach involves cross‐docking of 21 co‐crystal ligands with all the structures of the same protein to select structures that dock non‐native ligands with lower RMSD. The cross docking performance was then correlated with ligand similarity and binding‐site conformational similarity. Eventually, structures were shortlisted by integrating cross‐docking performance, and ligand and binding‐site similarity. Thereafter, binding pose metadynamics was employed to identify structures having stable co‐crystal ligands in their respective binding pockets. Finally, different enrichment metrics like BEDROC, RIE, AUAC, and EF1% were evaluated leading to the identification of five TMLR structures (5HCX, 5CAN, 5CAP, 5CAS, and 5CAO). These structures docked a number of non‐native ligands with low RMSD, contain structurally dissimilar ligands, have conformationally dissimilar binding sites, harbor stable co‐crystal ligands, and also identify true actives early. The present approach can be implemented for shortlisting protein targets of any other important therapeutic kinases.
Subject
Molecular Biology,Biochemistry
Cited by
1 articles.
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