title: Effects of variable docking conditions and scoring functions on corresponding protein-aligned comparative molecular field analysis models constructed from diverse human protein tyrosine phosphatase 1B inhibitors.
abstract: The effects of variable docking conditions and scoring functions on corresponding protein-aligned comparative molecular field analysis (CoMFA) models have been assessed. To this end, a group of diverse inhibitors were docked into the active site of human protein tyrosine phosphatase 1B (h-PTP 1B). The docked structures were utilized to construct corresponding protein-aligned CoMFA models by employing probe-based (H+, OH, CH3) energy grids and genetic partial least squares (G/PLS) statistical analysis. A total of 48 different docking configurations were evaluated, of which some succeeded in producing self-consistent and predictive CoMFA models. However, the best CoMFA model coincided with docking the un-ionized ligands into the hydrated form of the binding site via the PLP1 scoring function and restricted docking settings (r2(LOO) = 0.647, r2(PRESS) against 27 test compounds = 0.617). Interestingly, the most significant CoMFA models were orthogonal and corresponded to significantly different docked conformers/poses. To utilize the predictive potentials of the best CoMFA models collectively, it was decided to combine them in a single quantitative structure-activity relationship (QSAR) model. The combination model illustrated excellent statistical properties (r2(LOO) = 0.890, r2(PRESS) against 27 test compounds = 0.750).
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan. mutasem@ju.edu.jo
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
authors.forename: Murad A
authors.initials: MA
authors.lastname: AlDamen
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases