Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

SummaryA critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (α-helix, β-sheets, etc.; φ, ψ space) and those related to three-dimensional presentation of side-chain moieties (topography; χ (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.

[1]  D. M. Simons,et al.  Structure-Based Design of Synthetic Azobenzene Ligands for Streptavidin , 1994 .

[2]  R. Wade.  Peptides: Chemistry, structure and biology , 1977 .

[3]  W. C. Still,et al.  The multiple minimum problem in molecular modeling. Tree searching internal coordinate conformational space , 1988 .

[4]  Kit S. Lam,et al.  A new type of synthetic peptide library for identifying ligand-binding activity , 1992, Nature.

[5]  Charles R. Johnson,et al.  STRUCTURE-BASED DESIGN OF HIGH AFFINITY STREPTAVIDIN BINDING CYCLIC PEPTIDE LIGANDS CONTAINING THIOETHER CROSS-LINKES , 1995 .

[6]  K. Lam,et al.  Streptavidin and avidin recognize peptide ligands with different motifs , 1992 .

[7]  J. Devlin,et al.  Random peptide libraries: a source of specific protein binding molecules. , 1990, Science.

[8]  B. Katz,et al.  Binding to protein targets of peptidic leads discovered by phage display: crystal structures of streptavidin-bound linear and cyclic peptide ligands containing the HPQ sequence. , 1995, Biochemistry.

[9]  Norman L. Allinger,et al.  Molecular mechanics. The MM3 force field for hydrocarbons. 1 , 1989 .

[10]  K. Lam,et al.  A new type of synthetic peptide library for identifying ligand-binding activity , 1992, Nature.

[11]  R. Horváth,et al.  Probing the Stereochemical Requirements for Receptor Recognition of δ Opioid Agonists through Topographic Modifications in Position 1 , 1996 .

[12]  J. J. Wendoloski,et al.  Crystallographic and thermodynamic comparison of natural and synthetic ligands bound to streptavidin , 1992 .

[13]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[14]  V. Hruby,et al.  Asymmetric 1,4-addition of organocuprates to chiral .alpha.,.beta.-unsaturated N-acyl-4-phenyl-2-oxazolidinones: a new approach to the synthesis of chiral .beta.-branched carboxylic acids , 1993 .

[15]  R. Cass,et al.  Screening of cyclic peptide phage libraries identifies ligands that bind streptavidin with high affinities. , 1995, Biochemistry.

[16]  W. Kabsch.  A solution for the best rotation to relate two sets of vectors , 1976 .

[17]  R. Horváth,et al.  Newly discovered stereochemical requirements in the side-chain conformation of delta opioid agonists for recognizing opioid delta receptors. , 1994, Journal of medicinal chemistry.

[18]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[19]  V. Hruby,et al.  Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations. , 1990, The Biochemical journal.

[20]  P. Kollman,et al.  An all atom force field for simulations of proteins and nucleic acids , 1986, Journal of computational chemistry.

[21]  Jones Ml,et al.  Noncooperativity of biotin binding to tetrameric streptavidin. , 1995 .

[22]  V. Hruby,et al.  Locally constrained tyrosine analogues with restricted side chain dynamics , 1993 .

[23]  P. Weber,et al.  Crystal structure and ligand-binding studies of a screened peptide complexed with streptavidin. , 1992, Biochemistry.

[24]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[25]  J. Wendoloski,et al.  Structural origins of high-affinity biotin binding to streptavidin. , 1989, Science.

[26]  Thomas Kolter,et al.  Peptidomimetics for Receptor Ligands. Discovery, Development, and Medical Perspectives , 1993 .

[27]  V J Hruby,et al.  Conformational restrictions of biologically active peptides via amino acid side chain groups. , 1982, Life sciences.

[28]  Joseph M. Salvino,et al.  De novo design and synthesis of somatostatin non-peptide peptidomimetics utilizing beta-D-glucose as a novel scaffolding , 1993 .

[29]  V. Hruby,et al.  Stereoselective total synthesis of topographically constrained designer amino acids: 2′, 6′-dimethyl-β-methyltyrosines , 1995 .