Harnessing the druggability at orthosteric and allosteric sites of PD-1 for small molecule discovery by an integrated in silico pipeline

This study emphasizes the need for an integrated pipeline that uses molecular dynamics simulations and binding energetics to identify potential binders for the dynamic PD-1/PD-L1 interface, due to the lack of small molecule co-crystals. Only a few potential binders were discovered from a large pool of molecules targeting both the allosteric and orthosteric zones. Our results suggest that the allosteric site has more potential than the orthosteric site for inhibitor design. The identified "computational hits" hold potential as starting points for in vitro evaluations followed by hit-to-lead optimization. Overall, this study represents an effort to establish a computational pipeline for exploring and enriching both the allosteric and orthosteric sites of PPI interfaces, "a tough but indispensable nut to crack".PMID:37826990 | DOI:10.1016/j.compbiolchem.2023.107965
Source: Computational Biology and Chemistry - Category: Bioinformatics Authors: Source Type: research