Empowering AlphaFold2 for protein conformation selective drug discovery with AlphaFold2-RAVE.

ABSTRACT: Small molecule drug design hinges on obtaining co-crystallized ligand-protein structures. Despite AlphaFold2's strides in protein native structure prediction, its focus on apo structures overlooks ligands and associated holo structures. Moreover, designing selective drugs often benefits from the targeting of diverse metastable conformations. Therefore, direct application of AlphaFold2 models in virtual screening and drug discovery remains tentative. Here, we demonstrate an AlphaFold2 based framework combined with all-atom enhanced sampling molecular dynamics and induced fit docking, named AF2RAVE-Glide, to conduct computational model based small molecule binding of metastable protein kinase conformations, initiated from protein sequences. We demonstrate the AF2RAVE-Glide workflow on three

SUBMITTER: Gu X 

PROVIDER: S-EPMC11042445 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature