Docking flexible molecules: A case study of three proteins

Judson, Richard S.; Tan, Y. T.; Mori, Eigo; Melius, Carl F.; Jaeger, Edward P.; Treasurywala, Adi M.; Mathiowetz, Alan M.

doi:10.1002/jcc.540161109

Cited by 58 publications

(28 citation statements)

References 47 publications

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“…no crossover points inside the genes is equivalent to a real number representation. As pointed out by Judson,29 allowing crossovers inside the words would introduce large random mutations, slowing the search process. With regard to the mutation operator, a binary representation is similar to a real number representation with variable size mutations.…”

Section: Genetic Algorithmmentioning

confidence: 99%

Assessing search strategies for flexible docking

et al. 1998

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Section: Genetic Algorithmmentioning

confidence: 99%

Assessing search strategies for flexible docking

et al. 1998

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“…These X-ray data confirmed the mechanism of E 2 biosynthesis suggested earlier from biochemical experiments and revealed the topography of the enzyme binding site. E 2 binds in a narrow hydrophobic tunnel flanked at one end by Glu 282 and His 221 (the potential H-bonding counterparts for C 3 -OH group of E 2 ), and at the other end by Ser 142 and Tyr 155 (the counterparts for C 17 -OH group of E 2 ). The latter group is involved in the interaction with the nicotinamide moiety of NADP cofactor.…”

Section: Introductionmentioning

confidence: 99%

Monte Carlo-minimized energy profile of estradiol in the ligand-binding tunnel of 17?-hydroxysteroid dehydrogenase: Atomic mechanisms of steroid recognition

Zhorov

Lin

2000

Proteins

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17 beta-Estradiol (E2) is a potent stimulator of certain forms of breast cancer. The final step of E2 biosynthesis is catalyzed by the estrogenic 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD1), which is an important target for anti-cancer drugs. X-ray crystallography indicated that the binding site for the steroids has a tunnel-like shape. We have used a Monte Carlo-Minimization (MCM) protocol to explore possibilities of interactions of E2 with the binding site tunnel of 17 beta-HSD1. The enzyme was represented by flexible residues having at least one atom within 6 A from either E2 or NADP (as seen in a crystal ternary complex) and by rigid residues having at least one atom within 10 A from E2 or NADP. Special constraints were used to pull the substrate 10 A along the tunnel with 1 A step; the complex was MCM-optimized at each position of the steroid. The optimal binding mode of E2 in 17 beta-HSD agrees with the crystallographic data; however, wide and flat minima of the MCM profile suggest alternative modes of the steroid binding. The advance of the steroid along the tunnel is accompanied by essential conformational rearrangements of the enzyme side chains, noticeable rotation of the substrate along its longitudinal axis, and certain conformational deformations of the substrate. The contributions of the enzyme residues and of the steroid atoms to the intermolecular energy were estimated.

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“…6, 7 gorithms GAs have been used for flexible ligand docking. In these docking procedures, the flexibility was limited to the ligand while the binding site was kept fixed.…”

Section: Introduction Iochemical Specificity Relies On the Selectivementioning

confidence: 99%

Docking small ligands in flexible binding sites

1998

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A novel procedure for docking ligands in a flexible binding site is presented. It relies on conjugate gradient minimization, during which nonbonded interactions are gradually switched on. Short Monte Carlo minimization runs are performed on the most promising candidates. Solvation is implicitly taken into account in the evaluation of structures with a continuum model. It is shown that the method is very accurate and can model induced fit in the ligand and the binding site. The docking procedure has been successfully applied to three systems. The first two are the binding of progesterone and 5β‐androstane‐3,17‐dione to the antigen binding fragment of a steroid binding antibody. A comparison of the crystal structures of the free and the two complexed forms reveals that any attempt to model binding must take protein rearrangements into account. Furthermore, the two ligands bind in two different orientations, posing an additional challenge. The third test case is the docking of Nα‐(2‐naphthyl‐sulfonyl‐glycyl)‐D‐para‐amidino‐phenyl‐alanyl‐piperidine (NAPAP) to human α‐thrombin. In contrast to steroids, NAPAP is a very flexible ligand, and no information of its conformation in the binding site is used. All docking calculations are started from X‐ray conformations of proteins with the uncomplexed binding site. For all three systems the best minima in terms of free energy have a root mean square deviation from the X‐ray structure smaller than 1.5 Å for the ligand atoms. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 21–37, 1998

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Docking flexible molecules: A case study of three proteins

Cited by 58 publications

References 47 publications

Assessing search strategies for flexible docking

Assessing search strategies for flexible docking

Monte Carlo-minimized energy profile of estradiol in the ligand-binding tunnel of 17?-hydroxysteroid dehydrogenase: Atomic mechanisms of steroid recognition

Docking small ligands in flexible binding sites

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