Molecular Surfaces
9. Structure-Based Drug Design

Michael L. Connolly

1259 El Camino Real, #184
Menlo Park, CA 94025
U.S.A.

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http://www.netsci.org/Science/Compchem/feature14.html

One of the main purposes of identifying binding pockets on protein surfaces is to help in rational or structure-based drug design (Hansch and Klein, 1986; Kuntz, 1992; Navia and Murcko, 1992; Ring, Sun, McKerrow, Lee, Rosenthal, Kuntz and Cohen, 1993; Bugg, Carson and Montgomery, 1993; Murcko and Rotstein, 1993; Balbes, Mascarella and Boyd, 1994; Verlinde and Hol, 1994; Guida, 1994; Whittle and Blundell, 1994; Jackson, 1995; Hodge, Straatsma, McCammon and Wlodawer, 1996). After one has identified the possible binding regions on a protein surface, one can then move on to predicting which small molecules will bind to a cleft and in what orientation. This is called protein-ligand docking. One of the main efforts in this direction has been the DOCK project of Tack Kuntz and his students at the pharmaceutical chemistry department of the University of California at San Francisco (Kuntz, Blaney, Oatley, Langridge and Ferrin, 1982; DesJarlais, Sheridan, Dixon, Kuntz and Venkataraghavan, 1986; DesJarlais, Sheridan, Seibel, Dixon, Kuntz and Venkataraghavan, 1988; DesJarlais, Seibel, Kuntz, Furth, Alvarez, de Montellano, DeCamp, BabŽ and Craik, 1990; Shoichet, Bodian and Kuntz, 1992; Meng, Shoichet and Kuntz, 1992; Lewis, Roe, Huang, Ferrin, Langridge and Kuntz, 1992; Leach, and Kuntz, 1992; Shoichet and Kuntz, 1993; Meng, Gschwend, Blaney and Kuntz, 1993; Shoichet, Stroud, Santi, Kuntz and Perry, 1993; Kuntz, Meng and Shoichet, 1994; Grootenhuis, Roe, Kollman and Kuntz, 1994). Their software is distributed by the UCSF Molecular Design Institute. In this approach the binding site is modeled by a cluster of spheres, and then distance geometry (Crippen and Havel, 1988) is used to match the ligand atoms and the binding-site sphere cluster. Manavalan, Prabhakaran and Johnson (1992) have applied both DOCK and a grid-search method to sickle-cell hemoglobin.

Genetic algorithms have also been used for protein-ligand docking (Oshiro, Kuntz, Dixon, 1995). Clark and Ajay (1995) evaluated possible ligand dockings using an AMBER-type potential function. They first applied their method to docking rigid ligands and then extended it to flexible ligands. Judson, Tan, Mori, Melius, Jaeger, Treasurywala and Mathiowetz (1995) have applied a genetic algorithm conformation search method to dock flexible molecules into thermolysin, carboxypeptidase A, and dihydrofolate reductase. Gehlhaar, Verkhivker, Rejto, Sherman, Fogel, Fogel, Freer (1995) study the flexible docking of a proposed new drug into the HIV-1 protease using an evolutionary programming search technique. Teeter, Froimowitz, Stec and DuRand (1994) have proposed a model for the dopamine D2 receptor transmembrane helices and tried ddocking small molecules into it. Mizutani, Tomioka and Itai (1994) have developed a ligand-docking method that they have applied to dihydrofolate reductase and ribonuclease T1. Nauchitel, Villaverde and Sussman (1995) have used solvent-accessibility to study the binding of an inhibitor to HIV-1 protease. Another widely used method is Peter Goodford's GRID program (1985). This program studies the protein surface not with a neutral sphere, but rather with a more realistically shaped and charged probe. Probe molecules used include: water, the methyl group, amine nitrogen, carboxy oxygen, and hydroxyl. Surface contours are drawn at various energy levels, with negative-energy-level contours representing the attractive regions of the protein surface. The method incorporates hydrogen bonds (Wade, Clark and Goodford, 1993), and has been applied to DNA-drug interactions (Cruciani and Goodford, 1994). A combination of GRID and a standard molecular surface can be found at the University of Wisconsin.

The unpublished work of Dave Barry (Barry, 1983) at Washington University in St. Louis, suggested docking a stick figure into a solvent-accessible surface, that is, a surface with the atoms van der Waals radii expanded by the probe radius. Similar, but improved ideas have been put forth more recently (Bohacek and Guida, 1989; Bohacek and McMartin, 1992).

Besides docking small molecules of known structure to protein pockets, researchers also try to design or build up small molecules inside the pockets to maximize favorable contacts. Bohm (1992) has developed a program called LUDI for design possible enzyme inhibitors. Eisen, Wiley, Karplus and Hubbard (1994) have developed a method to create ligands that may bind to a given site. Gehlhaar, Moerder, Zichi, Sherman, Ogden and Freer (1995) have developed a method for the in situ generation of ligands for dihydrofolate reductase and thymidylate synthase. The design and flexible docking of peptides to proteins has also been studied (Gulukota, Vajda and DeLisi, 1996; Rosenfeld, Vajda and DeLisi, 1995). Instead of changing the ligand to fit the pocket, Hellinga, Caradonna and Richards (1991ab) change the pocket to fit the ligand.

A variety of other methods have also been developed: (Kuhl, Crippen and Friesen, 1984; Lawrence and Davis, 1992; Lybrand, 1995; Jones and Willett, 1995; Luty, Wasserman, Stouten, Hodge, Zacharis and McCammon, 1995). Also see the work done at The Scripps Research Institute (Goodsell and Olson, 1990; Goodsell, Lauble, Stout and Olson, 1993).

[ 1. Introduction ] [ 2. Physical Molecular Models ] [ 3. Electron Density Fitting ] [ 4. Molecular Graphics ] [ 5. Solvent-Accessible Surfaces ] [ 6. Molecular Surface Graphics ] [ 7. Molecular Volume and Protein Packing ] [ 8. Shapes of Small Molecules and Proteins ] [ *** 9. Structure-based Drug Design *** ] [ 10. Protein-Protein Interactions ] [ 11. Surface Biology, Chemistry and Physics ] [ 12. Bibliography ]

All material in ths article Copyright © 1996 by Michael L. Connolly



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