title: Enzyme isoselective inhibitors: application to drug design.
abstract: Common methodologies of computer-assisted drug design focus on noncovalent enzyme-ligand interactions. We introduced enzyme isoselective inhibition trend analysis as a tool for the expert analysis of covalent reversible inhibitors. The methodology is applied to predict the binding affinities of a series of transition-state analogue inhibitors of medicinally important serine and cysteine hydrolases. These inhibitors are isoselective: they have identical noncovalent recognition fragments (RS) and different reactive chemical fragments (CS). Furthermore, it is possible to predict the binding affinities of a series of isoselective inhibitors toward a prototype enzyme and to extrapolate the data to a target medicinally important enzyme of the same family. Rational design of CS fragments followed by conventional RS optimization could be used as a novel approach to drug design.
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel. shokhen@mail.biu.ac.il
authors.forename: Michael
authors.initials: M
authors.lastname: Shokhen
authors.forename: Netaly
authors.initials: N
authors.lastname: Khazanov
authors.forename: Amnon
authors.initials: A
authors.lastname: Albeck
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors