SMD-Based Interaction-Energy Fingerprints Can Predict Accurately the Dissociation Rate Constants of HIV-1 Protease Inhibitors.

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), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed.

Constructing Interconsistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.

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.

Allosteric effects of ATP binding on the nucleotide-binding domain of a heterodimeric ATP-binding cassette transporter.

ATP-binding cassette (ABC) exporters mediate vital transport of a variety of molecules across the lipid bilayer in all organisms. To explore the allosteric effect of ATP binding at the asymmetric ATPase sites, molecular dynamics simulations were performed on the nucleotide-binding domains (NBDs) of a heterodimeric exporter TM287/288 in 4 different ATP-bound states. The results showed that ATP bound at the degenerate site can maintain a semi-open conformation of NBD1-NBD2, which may be defective in ATP hydrolysis.

Prediction and characterization of P-glycoprotein substrates potentially bound to different sites by emerging chemical pattern and hierarchical cluster analysis.

P-glycoprotein (P-gp), an ATP-binding cassette (ABC) multidrug transporter, can actively transport a broad spectrum of chemically diverse substrates out of cells and is heavily involved in multidrug resistance (MDR) in tumors. So far, the multiple specific binding sites remain a major obstacle in developing an efficient prediction method for P-gp substrates. Herein, emerging chemical pattern (ECP) combined by hierarchical cluster analysis was utilized to predict P-gp substrates as well as their potential binding sites.

Subangstrom accuracy in pHLA-I modeling by Rosetta FlexPepDock refinement protocol.

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.