Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 30, Issue 12, Pages 1149-1163Publisher
SPRINGER
DOI: 10.1007/s10822-016-9984-2
Keywords
Chk1; Molecular dynamics simulation; Ligand receptor contact analysis; Pharmacophore
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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 angstrom) 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.
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