Calculation of binding free energies for non-zinc chelating pyrimidine dicarboxamide inhibitors with MMP-13.
All-atom molecular dynamics (MD) simulations in both explicit and implicit solvent, followed by MM-GBSA energy analysis, have been used to estimate binding free energies of four pyrimidine dicarboxamide inhibitors with human collagenase-3 (MMP-13) for comparison with experimental activities. Energetic analysis reveals that affinity is driven primarily by favorable van der Waals interactions and burial of total surface area. The computed effects of desolvation, as a function of ligand structure, quantitatively show that hydrophilic derivatives pay greater penalties upon binding than their related more hydrophobic analogs.
Carrascal
Noel
N
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794-3600, USA.
Rizzo
Robert C
RC
D000577:Amides; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008956:Models, Chemical; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D012997:Solvents; D013816:Thermodynamics
D000577:Amides; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D012997:Solvents; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13