Getting it right: modeling of pH, solvent and "nearly" everything else in virtual screening of biological targets.
"Getting it right" refers to the careful modeling of all elements in the living system, i.e. biological macromolecules, ligands and water molecules. In addition, careful attention should be paid to the protonation state of ionizable functional groups on the ligands and residues at the active site. Computational technology based on the empirical HINT program is described to: (1) calculate free energy scores for ligand binding; (2) include the implicit and explicit effects of water in and around the ligand binding site; and (3) incorporate the effects of global and local pH in molecular models. This last point argues for the simultaneous consideration of a number of molecular models, each with different protonation profiles. Data from recent studies of protein-ligand systems (trypsin, thrombin, neuraminidase, HIV-1 protease and others) are used to illustrate the concepts in the paper. Also discussed are experimental factors related to accurate free energy predictions with this and other computational technologies.
Kellogg
Glen E
GE
Department of Medicinal Chemistry, School of Pharmacy, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA. glen.kellog@vcu.edu
Fornabaio
Micaela
M
Spyrakis
Francesca
F
Lodola
Alessio
A
Cozzini
Pietro
P
Mozzarelli
Andrea
A
Abraham
Donald J
DJ
D001596:Benzylamines / Q000737:chemistry; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry; D011485:Protein Binding; D012984:Software; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry
D001596:Benzylamines; D008024:Ligands; D011480:Protease Inhibitors; D012997:Solvents; C094725:CGP 53820; D016333:HIV Protease; D014633:Valine