Method of rational drug design based on ab initio computer simul

Details Method of rational drug design based on ab initio computer simul Method of rational drug design based on ab initio computer simul

1995-04-21

1997-03-18

Voeltz, Emanuel T.

Boots, shoes, and leggings

364578, G06F 1542

Patent

active

056128959

ABSTRACT:
A method of rational drug design includes simulating polypeptides in a way that predicts the most probable secondary and/or tertiary structures of a polypeptide, e.g., an oligopeptide, without any presumptions as to the conformation of the underlying primary or secondary structure. The method involves computer simulation of the polypeptide, and more particularly simulating a real-size primary structure in an aqueous environment, shrinking the size of the polypeptide isobarically and isothermally, and expanding the simulated polypeptide to its real size in selected time periods. A useful set of tools, termed Balaji plots, energy conformational maps, and probability maps, assist in identifying those portions of the predicted peptide structure that are most flexible or most rigid. The rational design of novel compounds, useful as drugs, e.g., bioactive peptidomimetic compounds, and constrained analogs thereof, is thus made possible using the simulation methods and tools of the described invention.

REFERENCES:
patent: 4852017 (1989-07-01), Hunkapiller
patent: 4853871 (1989-08-01), Pantoliano et al.
patent: 4881175 (1989-11-01), Ladner
patent: 4908773 (1990-03-01), Pantoliano et al.
patent: 4939666 (1990-07-01), Hardman
patent: 5081584 (1992-01-01), Ominchinski et al.
patent: 5114918 (1992-05-01), Ishikawa et al.
patent: 5331573 (1994-07-01), Balaji et al.
patent: 5439812 (1995-08-01), Benkovic et al.
Allen, F.H., Acta Crystallography, B35:2231-2239 (1979).
Aumelas, et al., "Determination of the structure of [Nle.sup.7 ]-endothelin by .sup.1 H NMR," Int. J. Peptide Protein Res., 37:315-324 (1991).
Balasubramanian, R., "New type of representation for mapping chain folding in protein molecules," Nature, 266:856-857 (1974).
Blount, et al., "The dependence of the conformations of synthetic polypeptides on amino acid composition," J. Am. Chem. Soc. 82:3787-3789 (1960).
Brint, et al., J. Computer-Aided Molecular Design, 3:253 (1989).
Cooper, et al., J. Computer-Aided Molecular Design, 2:311 (1988).
Karplus, M., "Molecular Dynamics:Applications to Proteins in Computer Simulation of Chemical and Biochemical Systems," Annals N.Y. Acad. Sci., 482:255-266 (1986).
Kemp, D.S., "Peptidomimetics and the Template Approach to Nucleatio of .beta.-sheets and .alpha.-helices in peptides," Tibech, 8:249-255 (1990).
Kotelchuck & Scheraga, "The influence of short-range interactions on protein conformation, II. A model for predicting the .alpha.-helical regions of proteins," P.N.A.S. 62:14-21 (1969).
Pabo, et al., "Computer-Aided Model-Building Strategies for Protein Design," Biochemistry 25:5987-5991 (1986).
Perkins, et al., "Proposed solution structure of endothelin," Int. J. Peptide Protein Res., 36:128-133 (1990).
R.S., "Computerized Drug Design: Still Promising, Not Yet Here," Science 256:441 (1992).
Ramachandran, et al., "Conformation of Polypeptides," Adv. Prot. Chem., 23:283-437 (1968).
Saudek, et al., "Solution conformation of endothelin-1 by 1H NMR, CD, and molecular modeling," Int. J. Peptide Protein Res., 37:174-179 (1991).
Saudek, et al., ".sup.1 H-NMR study of endothelin, sequence-specific assignment of the spectrum and a solution structure," FEBS Letters, 257(1):145-148 (1989).
Szelke, et al., In Peptides: Structure & Funciton, Proceedings of 8th Amer. Peptide Symp., Hruby & Rich, Eds., Pierce Chemical Co., Rockford, III., pp. 579-582 (1983).
Weiner, et al., J. Comput. Chem., 7:230-252 (1986).
Weiner, et al., "A new force field for molecular mechanical simulation of nucleic acids abd proteins," J. Amer. Chem. Soc., 106(3):765-784 (1984).
Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Weinstein, Boris, Editor, Marcel Dekker, Inc., New York and Basel, Chapter 5, pp. 227-357 (1983).

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