Toward the Design of Allosteric Effectors: Gaining Comprehensive Control of Drug Properties and Actions.

ABSTRACT: While the therapeutic potential of allosteric drugs is increasingly realized, the discovery of effectors is largely incidental. The rational design of allosteric effectors requires new state-of-the-art approaches to account for the distinct characteristics of allosteric ligands and their modes of action. We present a broadly applicable computational framework for obtaining allosteric site-effector pairs, providing targeted, highly specific, and tunable regulation to any functional site. We validated the framework using the main protease from SARS-CoV-2 and the K-Ras^G12D oncoprotein. High-throughput per-residue quantification of the energetics of allosteric signaling and effector binding revealed known drugs capable of inducing the required modulation upon binding. Starting from

SUBMITTER: Tee WV 

PROVIDER: S-EPMC11472305 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature