Molecular dynamics (MD) based molecular mechanics Poisson-Boltzmann and surface area (MM-PB/SA) calculation (MD-PB/SA) has been widely used to estimate binding free energies for receptor-ligand complexes. While numerous reports have focused on assessing accuracy and efficiency, fewer studies have paid attention to performance in lead discovery. In the present study, we report a critical evaluat...

Sirtuins are key regulators of many cellular functions including cell growth, apoptosis, metabolism, and genetic control of age-related diseases. Sirtuins are themselves regulated by their cofactor nicotinamide adenine dinucleotide (NAD+) as well as their reaction product nicotinamide (NAM), the physiological concentrations of which vary during the process of aging. Nicotinamide inhibits sirtui...

Both KNI-10033 and KNI-10075 are high affinity preclinical HIV-1 protease (PR) inhibitors with affinities in the picomolar range. In this work, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the potency of these two HIV-1 PR inhibitors against the wild-type and mutated proteases assuming that potency correlates with the affinity of the drugs...

Protein-protein interactions, particularly weak and transient ones, are often mediated by peptide recognition domains, such as Src Homology 2 and 3 (SH2 and SH3) domains, which bind to specific sequence and structural motifs. It is important but challenging to determine the binding specificity of these domains accurately and to predict their physiological interacting partners. In this study, th...

Hepatitis C virus (HCV) causes an infectious disease that manifests itself as liver inflammation, cirrhosis, and can lead to the development of liver cancer. Its NS3/4A serine protease is a potent target for drug design and development since it is responsible for cleavage of the scissile peptide bonds in the polyprotein important for the HCV life cycle. Herein, the ligand-target interactions an...

With the rapid development of computational techniques and hardware, more rigorous and precise theoretical models have been used to predict the binding affinities of a large number of small molecules to biomolecules. By employing continuum solvation models, the MM/GBSA and MM/PBSA methodologies achieve a good balance between low computational cost and reasonable prediction accuracy. In this stu...

Human α-defensin 5 (HD5) is a broad-spectrum antibacterial peptide produced by small intestinal Paneth cells. Despite considerable experimental evidence for the correlation between bacterial membrane destruction and the antibacterial activity of HD5, its membrane disruption mechanism remains unclear. Using all-atom molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface...

Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our ...

The Poisson-Boltzmann equation is widely used for modeling the electrostatics of biomolecules, but the calculation results are sensitive to the choice of the boundary between the low solute dielectric and the high solvent dielectric. The default choice for the dielectric boundary has been the molecular surface, but the use of the van der Waals surface has also been advocated. Here we review rec...