title: Application of EMBM to Structure-Based Design of Warheads for Protease Inhibitors.
abstract: Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors. In the current study we demonstrate the utility of EMBM to structure-based applications. In this mode, the energy of the enzyme-inhibitor covalent bond is accounted for by the W1 and W2 covalent descriptors we have developed, whereas the non-covalent interactions between the inhibitor CS and the enzyme active site can be estimated directly on the 3D structure of the enzyme-inhibitor complex.
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel tel.: 972-3-5318862, fax: 972-3-7384053.
authors.forename: Tamar
authors.initials: T
authors.lastname: Traube
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel tel.: 972-3-5318862, fax: 972-3-7384053. michael.shokhen@biu.ac.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Shokhen
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel tel.: 972-3-5318862, fax: 972-3-7384053. amnon.albeck@biu.ac.il.
authors.forename: Amnon
authors.initials: A
authors.lastname: Albeck
keywords: Enzyme inhibitors; Proteases; Quantitative structure-activity relationship; Structure-based drug design; Transition-state analog