Targeting HIV-1 Envelope Proteins Using a Fragment Discovery All-Atom Computational Algorithm

Current Enzyme Inhibition
Michael H Peters

Abstract

HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains. A comprehensive, all-atom implicit solvent method is used to bombard the C-heptad repeat unit of HIV-1 target envelope protein GP41 with single D-amino acid residues as they exist in their native state. A nascent peptide computational search process then identifies potential favorable sequences of attached ligands based on four peptide bond criteria. Finally, dynamic simulations of nascent peptides attached to host targets help refine potential peptide inhibitors for experimental HIV-1 challenge assays and testing. Initial testing of the method was done using 64,000 total ligands of D-amino acid residues at a total computational time of 0.05 microseconds per ligand, which resulted in several thousand attached ligands. Peptid...Continue Reading

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AMBER

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