Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

A 5-μM docking hit has been optimized to an extraordinarily
potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase.
Use of free energy perturbation (FEP) calculations to predict relative
free energies of binding aided the optimizations by identifying optimal
substitution patterns for phenyl rings and a linker. The most potent
resultant catechol diethers feature terminal uracil and cyanovinylphenyl
groups. A halogen bond with Pro95 likely contributes to the extreme
potency of compound 42. In addition, several examples
are provided illustrating failures of attempted grafting of a substructure
from a very active compound onto a seemingly related scaffold to improve
its activity.