Molecular mechanisms and design principles for promiscuous inhibitors to avoid drug resistance: Lessons learned from HIV-1 protease inhibition
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Tidor_Molecular mechanisms.pdf
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Author(s)
Shen, Yang
Radhakrishnan, Mala L.
Tidor, Bruce
Date Issued
January 2015
Journal
Proteins: Structure, Function, and Bioinformatics
Publisher
Wiley Periodicals
Citation
Shen, Yang et al. “Molecular Mechanisms and Design Principles for Promiscuous Inhibitors to Avoid Drug Resistance: Lessons Learned from HIV-1 Protease Inhibition.” Proteins: Structure, Function, and Bioinformatics 83, 2 (January 2015): 351–372 © 2014 The Authors
Version
Author's final manuscript
Abstract
Molecular recognition is central to biology and ranges from highly selective to broadly promiscuous. The ability to modulate specificity at will is particularly important for drug development, and discovery of mechanisms contributing to binding specificity is crucial for our basic understanding of biology and for applications in health care. In this study, we used computational molecular design to create a large dataset of diverse small molecules with a range of binding specificities. We then performed structural, energetic, and statistical analysis on the dataset to study molecular mechanisms of achieving specificity goals. The work was done in the context of HIV-1 protease inhibition and the molecular designs targeted a panel of wild-type and drug-resistant mutant HIV-1 protease structures. The analysis focused on mechanisms for promiscuous binding to bind robustly even to resistance mutants. Broadly binding inhibitors tended to be smaller in size, more flexible in chemical structure, and more hydrophobic in nature compared to highly selective ones. Furthermore, structural and energetic analyses illustrated mechanisms by which flexible inhibitors achieved binding; we found ligand conformational adaptation near mutation sites and structural plasticity in targets through torsional flips of asymmetric functional groups to form alternative, compensatory packing interactions or hydrogen bonds. As no inhibitor bound to all variants, we designed small cocktails of inhibitors to do so and discovered that they often jointly covered the target set through mechanistic complementarity. Furthermore, using structural plasticity observed in experiments, and potentially in simulations, is suggested to be a viable means of designing adaptive inhibitors that are promiscuous binders.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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DOI of Published Version
https://doi.org/10.1002/prot.24730
