caa a22 4500 469053402 CHVBK 20180323132836.0 cr unu---uuuuu 170328e19920601xx s 000 0 eng 10.1007/BF00123378 doi (NATIONALLICENCE)springer-10.1007/BF00123378 An approach to computer-aided inhibitor design: Application to cathepsin L [Elektronische Daten] [Sucha Sudarsanam, G. Virca, Carl March, Subhashini Srinivasan] Summary: We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80 000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the ‘red tide' dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 μM and 0.6 μM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease. ESCOM Science Publishers B.V, 1992 Brevotoxin nationallicence Comparative modeling nationallicence Enzyme-inhibitor complex nationallicence Papain nationallicence Cysteine-protease nationallicence Sudarsanam Sucha Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A. aut Virca G. Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A. aut March Carl Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A. aut Srinivasan Subhashini Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A. aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 6/3(1992-06-01), 223-233 0920-654X 6:3<223 1992 6 10822 https://doi.org/10.1007/BF00123378 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00123378 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sudarsanam Sucha Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A aut NATIONALLICENCE 700 1- Virca G. Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A aut NATIONALLICENCE 700 1- March Carl Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A aut NATIONALLICENCE 700 1- Srinivasan Subhashini Department of Protein Chemistry, Immunex Corporation, 51 University Street, 98101, Seattle, WA, U.S.A aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 6/3(1992-06-01), 223-233 0920-654X 6:3<223 1992 6 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer