On the Mechanism of HRV-14 Antiviral Compounds: “Slow Growth” as a Conformational Search Procedure

Michael Guha-Biswas, Michael Holder, B. Montgomery Pettitt

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

We report a novel conformational search procedure that is used to investigate the binding mechanism of a member of the WIN class of antiviral compounds. A simple hypothesis of important residues in the binding site based on differences in drug-free and drug-bound X-ray structures along with more elaborate models, ultimately including the entire virus, is considered. Our search method is a variant of slow-growth molecular dynamics used in free energy simulations and gives rise to local motion in the protein backbone of up to 3 Å. This technique involves the scaling of drug-protein interaction energies over time periods of 10–100 ps and gives rise to local motion in the protein backbone. In addition, we have used high-temperature dynamics with periodic quenching to generate low-energy conformations with backbone displacements in the crystallographic binding region of up to 7 Å from the native structure. Mechanism of binding, hydrogen-bond stabilization of active-site conformations, concerted drug-protein motions, and the mode of virion stabilization are addressed in relation to our ligand induced and high-temperature conformational search procedures. A loop-cap like mechanism is consistent with the results of our study. A large movement of the “active-site” residues is shown to be theoretically possible and provides a greater access for entry of the drug into its binding pocket than seen in the available crystal structures.

Original languageEnglish (US)
Pages (from-to)3489-3495
Number of pages7
JournalJournal of Medicinal Chemistry
Volume36
Issue number23
DOIs
StatePublished - Nov 12 1993
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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