The human immunodeficiency virus 1 (HIV-1) protease (PR) is an aspartyl protease essential for HIV-1 viral infectivity. HIV-1 PR has one catalytic site formed by the homodimeric enzyme. We chemically synthesized fully active HIV-1 PR using modern ligation methods. When complexed with the classic substrate-derived inhibitors JG-365 and MVT-101, the synthetic HIV-1 PR formed crystals that diffracted to 1.04- and 1.2-A resolution, respectively. These atomic-resolution structures revealed additional structural details of the HIV-1 PR's interactions with its active site ligands. Heptapeptide inhibitor JG-365, which has a hydroxyethylamine moiety in place of the scissile bond, binds in two equivalent antiparallel orientations within the catalytic groove, whereas the reduced isostere hexapeptide MVT-101 binds in a single orientation. When JG-365 was converted into the natural peptide substrate for molecular dynamic simulations, we found putative catalytically competent reactant states for both lytic water and direct nucleophilic attack mechanisms. Moreover, free energy perturbation calculations indicated that the insertion of catalytic water into the catalytic site is an energetically favorable process.

2006-09-01·Journal of Chemical Theory and Computation1区 · 化学

Calculation of the Relative Binding Affinity of Enzyme Inhibitors Using the Generalized Linear Response Method

1区 · 化学

Article

作者: Tropsha, Alexander ; Chen, Xin

The generalized linear response (GLR) method initially developed for hydration free energy calculations has been adapted for binding free energy calculations. The calculations employ the concept of thermodynamic cycle. To obtain the value of the relative binding free energy between two ligands, we run molecular dynamics simulations at only four "midpoint" states along the thermodynamic pathways connecting the two ligands in the unbound and bound states, respectively. This approach significantly simplifies and accelerates the calculations as compared to the traditional free energy simulations where significantly more intermediate states are usually sampled. We show that each of these "midpoint" states can be approximately defined by a modified force field function in which both the van der Waals and electrostatic interactions between the variant part of a ligand and its environment, either binding site or aqueous solution, are scaled by a factor of 0.5. We tested this new approach to relative binding affinity calculations on the HIV-1 protease complex with its inhibitor JG365 as a starting point for the following two structural transformations: (a) the critical chiral center on the central residue was changed from (S) to (R) configuration, and (b) the C terminal valine residue was deleted. In both cases, the GLR method afforded calculated values that were in good agreement with the experimental data.

1999-12-01·Bioorganicheskaia khimiia

[Mechanism of aspartyl proteinase action. VII. Noncovalent complexes of HIV-1 aspartyl proteinase with substrate and substrate-like inhibitors].

Article

作者: Kashparov, I V ; Popov, M E ; Rumsh, L D ; Popov, E M

A computer model of a noncovalent complex of HIV-1 aspartyl protease with substrate-like inhibitor JG-365 was a priori constructed by using the approaches of theoretical conformational analysis and molecular mechanics. The root mean square deviation of the calculated conformation of the inhibitor from the X-ray diffraction analysis data was 0.87 A. These results enabled the a priori calculation of the structure of noncovalent complex of HIV-1 protease with a hexapeptide fragment of its native specific substrate Ser-Gln-Asn-Tyr-Pro-Ile-Val. The only possible orientation of the cleavable peptide bond in this and the nucleophilic water molecule relative to the catalytically active Asp residues of the enzyme (Asp25 and Asp125) was found that provides for the chemical transformation of the substrate to a tetrahedral intermediate. An action mechanism of enzymes of this class was proposed on the basis of the analysis of calculated distances. We showed that neither steric distortion of the cleavable bond nor the formation of unfavorable contacts in molecules of the enzymes and their substrates accompany the optimum orientation of substrate molecules at the active sites of HIV-1 aspartyl proteases and rhizopuspepsin.

100 项与 JG-365 相关的药物交易

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