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Drug-target residence time, the length of time for which a small molecule stays bound to its receptor target, has increasingly become a key property for optimization in drug discovery programs. However, its in silico prediction has proven difficult. Here we describe a method, using atomistic ensemble-based steered molecular dynamics (SMD), to observe the dissociation of ligands from their target G protein-coupled receptor in a time scale suitable for drug discovery. These dissociation simulations accurately, precisely, and reproducibly identify ligand-residue interactions and quantify the change in ligand energy values for both protein and water. The method has been applied to 17 ligands of the A

Drug-target residence time, the length of time for which a small molecule stays bound to its receptor target, has increasingly become a key property for optimization in drug discovery programs. However, its in silico prediction has proven difficult. Here we describe a method, using atomistic ensemble-based steered molecular dynamics (SMD), to observe the dissociation of ligands from their target G protein-coupled receptor in a time scale suitable for drug discovery. These dissociation simulations accurately, precisely, and reproducibly identify ligand-residue interactions and quantify the change in ligand energy values for both protein and water. The method has been applied to 17 ligands of the A2A adenosine receptor, all with published experimental kinetic binding data. The residues that interact with the ligand as it dissociates are known experimentally to have an effect on binding affinities and residence times. There is a good correlation ( R2 = 0.79) between the computationally calculated change in water-ligand interaction energy and experimentally determined residence time. Our results indicate that ensemble-based SMD is a rapid, novel, and accurate semi-empirical method for the determination of drug-target relative residence time.

Nonlinear two-dimensional infrared spectroscopy (2DIR) is most commonly simulated within the framework of the exciton method. The key parameters for these calculations include the frequency of the oscillators within their molecular environments and coupling constants that describe the strength of coupling between the oscillators. It is shown that these quantities can be obtained directly from harmonic frequency calculations by exploiting a procedure that localizes the normal modes. This approach is demonstrated using the amide I modes of polypeptides. For linear and cyclic diamides and hexapeptide Z-Aib-L-Leu-(Aib)2-Gly-Aib-OtBu, the computed parameters are compared with those from existing schemes, and the resulting 2DIR spectra are consistent with experimental observations. The incorporation of conformational averaging of structures from molecular dynamics simulations is discussed, and a hybrid scheme wherein the Hamiltonian matrix from the quantum chemical local-mode approach is combined with fluctuations from empirical schemes is shown to be consistent with experiment. The work demonstrates that localized vibrational modes can provide a foundation for the calculation of 2DIR spectra that does not rely on extensive parametrization and can be applied to a wide range of systems. For systems that are too large for quantum chemical harmonic frequency calculations, the local-mode approach provides a convenient platform for the development of site frequency and coupling maps.