Following the successful identification of lead inhibitors, compounds must be optimized for improved potency. Given the large search space possible, activity optimization can be made more efficient by computationally sampling functionality as well as biasing the search to favor molecules with specific desired properties. In this work, a series of HIV gp41 inhibitors recently identified in our laboratory through virtual screening is used as a test case towards development of inhibitor optimization protocols based on three main stages: (1) de novo design to sample new functionality at rationally selected attachment points on lead inhibitors, (2) flexible ligand docking to confirm binding pose compatibility, and (3) molecular dynamics simulations to estimate binding pose stability and energetics.  Preliminary results suggest the protocol will be useful to aid the identification of well-behaved closely-related analogs with desired properties for further study.

Strategies for lead inhibitor optimization: Application to HIVgp41

247th National Meeting (2014)

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