Hydrophobicity maps and docking of molecular fragments with solvation

NICOLAS MAJEUX, MARCO SCARSI, CATHERINE TENETTE-SOUAILLE and AMEDEO CAFLISCH*

Department of Biochemistry, University of Zürich, Winterthurerstraße 190, CH-8057 Zürich, Switzerland

Summary. Two methods for structure-based computational ligand design are reviewed. Hy-drophobicity maps allow to quantitatively estimate and graphically display the propensity of nonpolar groups to bind at the surface of a protein target [Scarsi et al., Proteins Struct. Funct. Genet., 37 (1999) 565]. The program SEED (Solvation Energy for Exhaustive Docking) finds optimal positions and orientations ofnonpolar fragments using the hydrophobicity maps, while polar fragments are docked with at least one hydrogen bond with the protein [Majeux et al., Proteins Struct. Funct. Genet., 37 (1999) 88]. An efficient evaluation of the binding energy, including continuum electrostatic solvation, allows to dock a library of 100 fragments into a 25-residue binding site in about five hours on a personal computer. Applications to thrombin, a key enzyme in the blood coagulation cascade, and the p38 mitogen-activated protein kinase, which is a target for the treatment of inflammatory and neurodegenerative diseases, are presented. The role of the hydrophobicity maps and structure-based docking of a fragment library in exploiting genomes to design drugs is addressed.

Key words: continuum electrostatics, docking of fragment library, generalized Born approximation, hydrophobicity map, molecular surface, p38 MAP kinase, SEED, solvation, thrombin

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