title: Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies.
abstract: Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified. Ligand-receptor contacts maintained above certain threshold during molecular dynamics simulation are considered critical and used to guide pharmacophore development. We termed this method as Molecular-Dynamics Based Ligand-Receptor Contact Analysis. We implemented this new methodology to develop valid pharmacophore models for check point kinase 1 (Chk1) and beta-secretase 1 (BACE1) inhibitors as case studies. The resulting pharmacophore models were validated by receiver operating characteristic curved analysis against inhibitors obtained from CHEMBL database.
authors.affiliation: Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan.
authors.forename: Ma'mon M
authors.initials: MM
authors.lastname: Hatmal
authors.affiliation: Department of Medical Analysis, Faculty of Allied Health Sciences, Zarqa Private University, Zarqa, Jordan.
authors.forename: Shadi
authors.initials: S
authors.lastname: Jaber
authors.affiliation: Drug Discovery Unit, 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
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D054852:Small Molecule Libraries / Q000737:chemistry
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D000071877:Checkpoint Kinase 1; D053829:Amyloid Precursor Protein Secretases
keywords: Chk1; Ligand receptor contact analysis; Molecular dynamics simulation; Pharmacophore