Specificity in Molecular Design: Probing the Intrinsic and Extrinsic Determinants of Binding Specificity and Promiscuity

Mala Radhakrishnan, Massachusetts Institute of Technology

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An effective drug must bind with high specificity to its intended target in the body; if not, deleterious side effects might occur. However, if the target is rapidly mutating, like HIV-1 protease, a drug that is too specific will quickly lose its efficacy by not binding well to functional mutants. Therefore, in molecular design, it is crucial to tailor the binding specificity of a drug to the problem at hand. In this study, we seek to understand how intrinsic physical characteristics of a molecule — including charge distribution, shape, size, and flexibility — might affect its innate “promiscuity”, or its ability to bind equally well to many partners. We also study how certain external factors, such as the characteristics of the possible binding partners, affect the promiscuities of ligands. By creating a simplified model that captures some of the key contributions to binding and extending a theoretical framework grounded in continuum electrostatics, we demonstrate, both theoretically and numerically, that there are definitive ways in which a molecule’s specificity depends on its intrinsic and extrinsic characteristics. Taken together, these factors form a physical basis that can be applied in the design of molecules with tailored specificities, leading to more potent therapeutics.

Abstract Author(s): Mala L. Radhakrishnan and Bruce Tidor