Accumulated evidence suggests that the in vivo biological potency of a ligand is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of the protein-ligand interaction (PLI). However, the existing experimental and computational techniques are largely insufficient and limited in large-scale measurements or accurate predictions of the kinetic properties of PLI. In this work, elaborate efforts have been made to develop interconsistent, reasonable, and predictive models of the association rate constant (k), dissociation rate constant (k), and equilibrium dissociation constant (K) of a series of HIV protease inhibitors with different structural skeletons. The results showed that nine Volsurf descriptors derived from water (OH2) and hydrophobic (DRY) probes are key molecular determinants for the kinetic and thermodynamic properties of HIV-1 protease inhibitors. To the best of our knowledge, this is the first time that interconsistent and reasonable models with strong prediction power have been established for both the kinetic and thermodynamic properties of HIV protease inhibitors.
Flexible peptides binding to human leukocyte antigen (HLA) play a key role in mediating human immune responses and are also involved in idiosyncratic adverse drug reactions according to recent research. However, the structural determinations of pHLA complexes remain challenging under the present conditions. In this paper, the performance of a new peptide docking method, namely FlexPepDock, was systematically investigated by a benchmark of 30 crystallized structures of peptide-HLA class I complexes. The docking results showed that the near-native pHLA-I models with peptide bb-RMSD less than 2 Å were ranked in the top 1 model for 100% (70/70) docking cases, and the subangstrom models with peptide bb-RMSD less than 1 Å were ranked in the top 5 lowest-energy models for 65.7% (46/70) docking cases. Furthermore, 10 out of 70 docking cases ranked the subangstrom all-atom models in the top 5 lowest-energy models. The results showed that the FlexPepDock can generate high-quality models of pHLA-I complexes and can be widely applied to pHLA-I modeling and mechanism research of peptide-mediated immune responses.
Recent research has increasingly suggested that the crucial factors affecting drug potencies are related not only to the thermodynamic properties but also to the kinetic properties. Therefore, in silico prediction of ligand-binding kinetic properties, especially the dissociation rate constant (k off ), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed. In this paper, steered molecular dynamics (SMD) combined with residue-based energy decomposition was employed to predict the dissociation rate constants of 37 HIV-1 protease inhibitors (HIV-1 PIs). For the first time, a predictive model of the dissociation rate constant was established by using the interaction-energy fingerprints sampled along the ligand dissociation pathway. On the basis of the key fingerprints extracted it can be inferred that the dissociation rates of 37 HIV-1 PIs are basically determined in the first half of the dissociation processes and that the H-bond interactions with active-site Asp25 and van der Waals interactions with flap-region Ile47 and Ile50 have important influences on the dissociation processes. In general, the strategy established in this paper can provide an efficient way for the prediction of dissociation rate constants as well as the unbinding mechanism research.
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