title: Prediction of new serine proteinase inhibitors.
abstract: We describe here the use of a rapid computational method to predict the relative binding strengths of a series of small-molecule ligands for the serine proteinase trypsin. Flexible molecular models of the ligands were docked to the proteinase using an all-atom potential set, without cutoff limits for the non-bonded and electrostatic energies. The binding-strength calculation is done directly in terms of a molecular mechanics potential. The binding of eighteen different compounds, including non-binding controls, has been successfully predicted. The measured Ki is correlated with the predicted energy. The correctness of the theoretical calculations is demonstrated with both kinetics measurements and X-ray structure determination of six enzyme-inhibitor complexes.
authors.affiliation: Department of Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: I V
authors.initials: IV
authors.lastname: Kurinov
authors.forename: R W
authors.initials: RW
authors.lastname: Harrison
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014361:Trypsin Inhibitors