Relative differences in the binding free energies of human immunodeficiency virus 1 protease inhibitors: a thermodynamic cycle-perturbation approach.

Abstract

Peptidomimetic inhibitors of the human immunodeficiency virus 1 protease show considerable promise for treatment of AIDS. We have, therefore, been seeking computer-assisted drug design methods to aid in the systematic design of such inhibitors from a lead compound. Here we report thermodynamic cycle-perturbation calculations (using molecular dynamics simulations) to compute the relative difference in free energy of binding that results when one entire residue (valine) is deleted from one such inhibitor. In particular, we studied the "alchemic" mutation of the inhibitor Ac-Ser-LeuAsn-(Phe-Hea-Pro)-Ile-Val-OMe (S1) to Ac-Ser-Leu-Asn-(PheHea-Pro)-Ile-OMe (S2), where Hea is hydroxyethylamine, in two different (R and S) diastereomeric configurations of the hydroxyethylene group. The calculated (averaged for R and S) difference in binding free energy [3.3 + 1.1 kcal/mol (mean ± SD); 1 cal = 4.184 J] is in good agreement with the experimental value of 3.8 ± 1.3 kcal/mol, obtained from the measured K; values for an equilibrium mixture of R and S configurations. Precise testing of our predictions will be possible when binding data become available for the two disastereomers separately. The observed binding preference for S1 is explained by the stronger ligand-protein interaction, which dominates an opposing contribution arising from the large desolvation penalty of S1 relative to S2. This calculation suggests that the thermodynamic cycle-perturbation approach can be useful even when a relatively large change in the ligand is simulated and supports the use of the thermodynamic cycle-perturbation algorithm for screening proposed derivatives of a lead inhibitor/drug prior to their synthesis.

Calculation of relative binding affinities of fructose 1,6‐bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

“…8 The most accurate computational method for estimating relative binding affinities of structurally similar inhibitors to an enzyme is the free energy perturbation (FEP) approach using with either molecular dynamics (MD) or Monte Carlo (MC) simulations. 9 Despite its high accuracy, free energy calculations have primarily been used to rationalize experimentally determined binding affinities [10][11][12][13][14] with few applications focusing on predictions. [15][16][17][18] This article presents our efforts to utilize computer-aided drug design approaches, particularly, FEP method for estimating relative binding affinities for five pairs of mutant and wild-type structures of the FBPase:AMP complex and compare the free energy results with experimentally determined binding affinities.…”

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

“…FEP guided studies on HIV-1 PR inhibition began in the early 1990s [72], made possible by the determination of HIV-1 protein-inhibitor crystal structures [73,74], and primarily focused on rationalizing the known binding affinities between closely related polypeptide-based inhibitors. For example, in 1991 Reddy et al [75] used an FEP/MD approach to mutate the inhibitor ligand by deleting the hydrophobic residue valine of the JG-365 heptapeptide inhibitor Ac-Ser-Leu-Asn-(Phe-HeaPro)-Ile-Val-OMe made by Rich et al [76] (Fig. 2A) to create the hexapeptide Ac-Ser-LeuAsn-(Phe-Hea-Pro)-Ile-OMe (where Hea is hydroxyethylamine).…”

Prediction of Relative Stability between TACE/Gelastatin and TACE/Gelastatin Hydroxamate

“…[6][7] A free energy simulation technique known as the thermodynamic cycle perturbation (TCP) approach [8][9][10][11] used in conjunction with molecular dynamics calculations offers a theoretically precise method of determining the binding free energy differences of structurally related inhibitors. Despite its high accuracy, free energy calculations [12][13][14][15][16][17] have primarily been used to rationalize experimentally determined binding affinities rather than predict affinities of new analogues. The reluctance to use free energy calculations for predictions and therefore drug design is partly § Member of Translational Research Center for Protein Function Control, Korea.…”