title: On the rational design of substrate mimetics: The function of docking approaches for the prediction of protease specificities.
abstract: The behaviour of substrate mimetics in mediating the acceptance of nonspecific acyl moieties by proteases has been investigated as a direct function of their site-specific ester leaving groups. In this contribution we report on a computational approach to rationalise this interplay and to predict the power of a potential ester moiety to act as a suitable substrate mimetic for a given enzyme by means of an automated docking procedure. Investigations with seven distinct substrate mimetics and two proteases, subtilisin and chymotrypsin, show a clear correlation between the theoretically calculated binding energies DeltaE and the specificity constants k(cat)KM(-1) obtained from parallel hydrolysis kinetic studies. These results prove the general function of the docking approach as a rational model not only in predicting the general acceptance of a substrate mimetic in a qualitative manner, but also to provide reliable information on its individual specificity towards proteases.
authors.affiliation: University of Leipzig, Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Bruderstr. 34, D-04103 Leipzig, Germany. robguent@uni-leipzig.de
authors.forename: Robert
authors.initials: R
authors.lastname: Günther
authors.forename: Christian
authors.initials: C
authors.lastname: Elsner
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Hofmann
authors.forename: Frank
authors.initials: F
authors.lastname: Bordusa
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives; D024322:Amino Acids, Aromatic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D002918:Chymotrypsin / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D004952:Esters / Q000138:chemical synthesis / Q000378:metabolism; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D055672:Static Electricity; D013379:Substrate Specificity; D020860:Subtilisin / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D024322:Amino Acids, Aromatic; D004952:Esters; D010450:Endopeptidases; D002918:Chymotrypsin; D020860:Subtilisin; D000409:Alanine