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

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.