Toward the\nDesign of Allosteric Effectors: Gaining\nComprehensive Control of Drug Properties and Actions

While the therapeutic potential of allosteric drugs is\nincreasingly\nrealized, the discovery of effectors is largely incidental. The rational\ndesign of allosteric effectors requires new state-of-the-art approaches\nto account for the distinct characteristics of allosteric ligands\nand their modes of action. We present a broadly applicable computational\nframework for obtaining allosteric site–effector pairs, providing\ntargeted, highly specific, and tunable regulation to any functional\nsite. We validated the framework using the main protease from SARS-CoV-2\nand the K-Ras<sup>G12D</sup> oncoprotein. High-throughput per-residue\nquantification of the energetics of allosteric signaling and effector\nbinding revealed known drugs capable of inducing the required modulation\nupon binding. Starting from fragments of known well-characterized\ndrugs, allosteric effectors and binding sites were designed and optimized\nsimultaneously to achieve targeted and specific signaling to distinct\nfunctional sites, such as, for example, the switch regions of K-Ras<sup>G12D</sup>. The generic framework proposed in this work will be\ninstrumental in developing allosteric therapies aligned with a precision\nmedicine approach.