title: Evaluation and application of MD-PB/SA in structure-based hierarchical virtual screening.
abstract: 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 evaluation of MD-PB/SA in hierarchical virtual screening (HVS) both theoretically and practically. It is shown that based on native poses, MD-PB/SA could be well applied to predict the relative binding energy for both congeneric and diverse ligands for different protein targets. However, there is a limitation for MD-PB/SA to distinguish the native pose of one ligand from the artificial pose of another when a huge difference exists between two molecules. By combining a physics-based scoring function with a knowledge-based structural filter, we improve the predictability and validate the practical use of MD-PB/SA in lead discovery by identifying novel inhibitors of p38 MAP kinase. We also expand our study to other protein targets such as HIV-1 RT and NA to assess the general validity of MD-PB/SA.
authors: National Institute of Biological Sciences, Beijing , No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China.
authors: Ran
authors: R
authors: Cao
authors: Niu
authors: N
authors: Huang
authors: Yanli
authors: Y
authors: Wang
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012997:Solvents / Q000737:chemistry; D014584:User-Computer Interface; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D012997:Solvents; D048051:p38 Mitogen-Activated Protein Kinases; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D009439:Neuraminidase