Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method

Monte Carlo (MC) simulations in combination with a linear response approach were used to estimate the free energies of binding for a series of 12 TIBO nonnucleoside inhibitors of HIV-1 reverse transcriptase. Separate correlat ions were made for the R-6 and S-6 absolute conformations of the inhibitors , as well as for the analogous N6-monoprotonated species. Models based upon the neutral unbound inhibitors produced overall better fits to experimenta l values than did those using the protonated unbound inhibitors, with only slight differences between the neutral R-6 and S-6 cases. The best results were obtained with a three-parameter linear response equation containing va n der Waals (alpha), electrostatic (beta), and solvent accessible surface a rea (SASA, gamma) terms. The averaged (R-6 and S-6) rms error was approxima tely 0.88 kcal/mol for the observed range of 4.06 kcal/mol in inhibitor act ivities. The averaged values of alpha, beta, and gamma mere -0.150, 0.114, and 0.0286, respectively. Omission of the alpha term gave beta 0.152 and ga mma 0.022 with a rms of 0.92. The unweighted van der Waals components were found to be highly attractive but failed to correlate well across the serie s of inhibitors. Contrastingly, while the electrostatic components are all repulsive, they show a direct correlation with inhibitor activity as measur ed by Delta G(binding). The role of gamma is primarily to produce an overal l negative binding energy, and it can effectively be replaced with a negati ve constant. During the MC simulations of the unbound solvated inhibitors, the R-6 and S-6 absolute conformations do not interconvert; due to the form ation of a favorable hydrogen bond to solvent. In the complex, however, int erconversion of these conformations of the inhibitor is observed during the course of the simulations, a phenomenon which is apparently not observed i n the crystalline state of the complex. Hydrogen bonding of the inhibitor t o the backbone NH of K101 and the lack of such an interaction with the C=O of K101 or with solvent correlate with enhanced activity, as does the abili ty to assume a number of different orientations of the inhibitor dimethylal lyl moiety with respect to residues Y181 and Y188 while retaining contact w ith W229. Overall, the use of a combination of MC simulation with a linear response method shows promise as a relatively rapid means of estimating inh ibitor activities. This approach should be useful in the preliminary evalua tion of potential modifications to known inhibitors to enhance activity.