Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRAS ^G12D.

ABSTRACT: Identification of cryptic pockets has the potential to open new therapeutic opportunities by discovering ligand binding sites that remain hidden in static apo structures of a target protein. Moreover, allosteric cryptic pockets can become valuable for designing target-selective ligands when the natural ligand binding sites are conserved in variants of a protein. For example, before an allosteric cryptic pocket was discovered, KRAS was considered undruggable due to its smooth surface and conservation of the GDP/GTP binding pocket across the wild type and oncogenic isoforms. Recent identification of the Switch-II cryptic pocket in the KRAS^G12C mutant and FDA approval of anticancer drugs targeting this site underscores the importance of cryptic pockets in solving pharmaceutical cha

SUBMITTER: Vithani N 

PROVIDER: S-EPMC11558672 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature