It is imperative that alternative inhibitors of Human Immunodeficiency Virus (HIV) gp41, a protein that plays a central role in viral entry, be developed as the emergence of drug-resistant mutations have significantly reduced the efficacy of current anti-retroviral therapeutics. Small-molecule inhibitors targeting more conserved regions have been reported as demonstrating activity against HIV gp41. However, refinement of these inhibitors has proven to be difficult as a result of the limited experimental structural information available on small-molecule binding. The goals of this work are to develop a robust computational protocol that can be used to: i) validate the geometry of ligand-bound structures and ii) improve the potency and selectivity of small-molecule inhibitors. The protocol encompasses molecular docking, <i>de novo</i> design, genetic algorithm and rigorous free-energy calculations to compute the relative free energies between closely related ligand pairs. This will aid in the selection and design of new potential inhibitors. The development of protocols as such will be valuable in not only improving inhibitors of gp41 but of other biological systems as well.

Computational approaches to aid the design of small-molecule HIV gp41 inhibitors

251st National Meeting (2016)

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