Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HTV protease |
| |
| Authors: | Tropsha Alexander; Hermans Jan |
| |
| Affiliation: | 1Division of Medicinal Chemistry and Natural Products School of Pharmacy, and Brain and Development Research Center, School of Medicine
2Department of Biochemistry and Biophysics School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA |
| |
| Abstract: | Free energy simulations (slow-change method) have been usedto estimate quantitatively the ratio of the binding constantsof (S) and (R) isomers of a novel HIV protease inhibitor, JG365.As a starting geometry, we used the X-ray crystallographic structureof a complex of HTV protease and JG365 provided by A.Wlodawer.According to our results the (S) configuration, i.e. the formpreviously identified experimentally, binds considerably moretightly to the protease (G° = 2.9 kcal/mol). When the (S)inhibitor is bound, there is a very strong preference for protonationof the Aspl25 (rather than the Asp25) residue of the protease.This study is the first to apply a new method for quantitativelyassessing the precision of free energies calculated by the slow-changemethod |
| |
| Keywords: | binding constants/ free energy simulations/ HIV/ protease inhibitors/ slow-change method |
| 本文献已被 Oxford 等数据库收录！ |
|
