Professor Carol B. Post
Department of Medicinal Chemistry and Pharmacognosy
Purdue University
West Lafayette, IN

Monday, March 29, 1999
3:00 pm (CT)
3269 Beckman Institute

Abstract

Antipicornaviral compounds bind an internal pocket located in the VP1 protein subunit of the viral capsid. The three-dimensional structures of numerous antiviral complexes of human rhino virus (HRV) and polio virus, as well as the effects of the antiviral compounds on the virus lifecycle, have been known for several years. The antiviral activity of most of these compounds arises from stabilization of the viral capsid and inhibition of viral uncoating. In an attempt to understand the physical basis for the antiviral effects of these compounds, and thus to aid in the development of improved antiviral compounds, we recently conducted several molecular dynamics simulations on HRV14. A reduced system of the virus, focused on the drug-binding pocket, was used to simulate unligated HRV14 and HRV14 bound with the antiviral compound WIN52084s. Detailed analysis of compressibility, temperature dependence of fluctuations, energy components, and correlated motions have lead us to propose a previously unrecognized basis for the experimentally observed stabilization against viral uncoating. The simulation results are most consistent with an entropic basis for stabilization; the antiviral complex is of higher entropy than the unligated virus due to a change in interatomic interactions being more nonpolar in nature when drug occupies the binding pocket than in the absence of drug.

Tea and coffee will be served in R3151 Beckman Institute at 2:15pm.