Computational Drug Design with Application to HIV/AIDS and Cancer

Recent computational approaches aimed at quantifying and understanding molecular recognition events associated with anti-HIV and anti-Cancer drugs will be presented.

(1) All-atom molecular simulations have been performed to evaluate the binding energies for over 200 inhibitors with the HIV reverse transcriptase (HIVRT) enzyme using a procedure called extended linear response (ELR). Through examination of energetic and structural simulation results, these calculations provide a framework for understanding variations in binding affinities.

(2) We have also studied the problem of HIV drug resistance using docking/free energy perturbation methods to predict, validate, and rationalize a complex of HIVRT with Sustiva through computation of resistance profiles.

(3) Finally, we have used recent MM-GBSA methods to elucidate a molecular basis for the experimentally observed selectivities of inhibitors for matrix metalloproteinases, stromelysin-1 and gelatinase-A, which have been implicated in a variety of cancers.

In general, the computational approaches described in this talk could be applied to study molecular recognition events associated with many different targets of therapeutic interest.

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