title: Protein tyrosine phosphatases: Ligand interaction analysis and optimisation of virtual screening.
abstract: Docking-based virtual screening is an established component of structure-based drug discovery. Nevertheless, scoring and ranking of computationally docked ligand libraries still suffer from many false positives. Identifying optimal docking parameters for a target protein prior to virtual screening can improve experimental hit rates. Here, we examine protocols for virtual screening against the important but challenging class of drug target, protein tyrosine phosphatases. In this study, common interaction features were identified from analysis of protein-ligand binding geometries of more than 50 complexed phosphatase crystal structures. It was found that two interactions were consistently formed across all phosphatase inhibitors: (1) a polar contact with the conserved arginine residue, and (2) at least one interaction with the P-loop backbone amide. In order to investigate the significance of these features on phosphatase-ligand binding, a series of seeded virtual screening experiments were conducted on three phosphatase enzymes, PTP1B, Cdc25b and IF2. It was observed that when the conserved arginine and P-loop amide interactions were used as pharmacophoric constraints during docking, enrichment of the virtual screen significantly increased in the three studied phosphatases, by up to a factor of two in some cases. Additionally, the use of such pharmacophoric constraints considerably improved the ability of docking to predict the inhibitor's bound pose, decreasing RMSD to the crystallographic geometry by 43% on average. Constrained docking improved enrichment of screens against both open and closed conformations of PTP1B. Incorporation of an ordered water molecule in PTP1B screening was also found to generally improve enrichment. The knowledge-based computational strategies explored here can potentially inform structure-based design of new phosphatase inhibitors using docking-based virtual screening.
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain 64141, United Arab Emirates.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghattas
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain 64141, United Arab Emirates.
authors.forename: Noor
authors.initials: N
authors.lastname: Atatreh
authors.affiliation: Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Bichenkova
authors.affiliation: Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Electronic address: richard.bryce@manchester.ac.uk.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D014584:User-Computer Interface; D014867:Water / Q000737:chemistry; D014965:X-Rays
chemical_list: D008024:Ligands; D014867:Water; D017027:Protein Tyrosine Phosphatases
keywords: Constraint; Docking; PTP1B; Pharmacophore; Protein tyrosine phosphatase; Virtual screening