Tee, W.-V., Lim, S. J. M., & Berezovsky, I. N. (2024). Toward the Design of Allosteric Effectors: Gaining Comprehensive Control of Drug Properties and Actions. Journal of Medicinal Chemistry, 67(19), 17191–17206. https://doi.org/10.1021/acs.jmedchem.4c01043
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-RasG12D 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 fragments of known well-characterized drugs, allosteric effectors and binding sites were designed and optimized simultaneously to achieve targeted and specific signaling to distinct functional sites, such as, for example, the switch regions of K-RasG12D. The generic framework proposed in this work will be instrumental in developing allosteric therapies aligned with a precision medicine approach.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the A*STAR Research Office - Career Development Fund
Grant Reference no. : A*STAR C210812031
This research / project is supported by the National Medical Research Council (NMRC) - Open-Fund Individual Research Grant (OF-IRG)
Grant Reference no. : MOH-001402-00