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In this work, a new ansatz is presented that combines molecular dynamics simulations with MM-PBSA (Molecular Mechanics Poisson−Boltzmann/surface area) to rank the binding affinities of 12 TIBO-like HIV-1 RT inhibitors. Encouraging results have been obtained not only for the relative binding free energies, but also for the absolute ones, which have a root-mean-square deviation of 1.0 kcal/mol (the maximum error is 1.89 kcal/mol). Since the root-mean-square error is rather small, this approach can be reliably applied in ranking the ligands from the databases for this important target. Encouraged by the results, we decided to apply MM-PBSA combined with molecular docking to determine the binding mode of efavirenz SUSTIVA^TM another promising HIV-1 RT inhibitor for which no ligand−protein crystal structure had been published at the time of this work. To proceed, we define the following ansatz:  Five …