Jeffrey M. Blaney

A geometric approach to macromolecule-ligand interactions.

Abstract We describe a method to explore geometrically feasible alignments of ligands and receptors of known structure. Algorithms are presented that examine many binding geometries and evaluate them in terms of steric overlap. The procedure uses specific molecular conformations. A method is included for finding putative binding sites on a macromolecular surface. Results are reported for two systems: the heme-myoglobin interaction and the binding of thyroid hormone analogs to prealbumin. In each case the program finds structures within 1 A of the X-ray results and also finds distinctly different geometries that provide good steric fits. The approach seems well-suited for generating starting conformations for energy refinement programs and interactive computer graphics routines.

A good ligand is hard to find: Automated docking methods

Many approaches have been developed for solving the ‘docking problem’: Predict the structure and binding free energy of a ligand-receptor complex given only the structures of the free ligand and receptor. We review major approaches for docking small-molecule ligands to receptors and focus on the successes and limitations of their application to drug design.

Computational approaches for combinatorial library design and molecular diversity analysis.

New approaches for combinatorial library design and molecular diversity analysis have been developed by extending previous work from the fields of quantitative structure-activity relationship, computational chemistry, and chemical information. Recent work has begun to address design efficiency and validation of descriptors for combinatorial library design.

Conformational analysis using distance geometry methods

Distance geometry methods have been used extensively to build models of molecules of various sizes, including small molecules, peptides, and proteins. These methods are often overlooked as tools for conformational analysis, even though they often perform as well as other conformational sampling methods. We have implemented two new distance geometry approaches in the DGEOM95 package. In the first new method, the traditional embedding algorithm is replaced with a procedure that generates random 4D coordinates for each atom, followed by refinement of these coordinates into 3D using the distance geometry error function. The conformational sampling produced by this method is comparable to that obtained with partial metrization, and superior to that obtained with the original embedding procedure. In the second method, a molecular dynamics step is included in the refinement stage. Although this method can be applied to any embedding algorithm, substantial improvements in sampling are seen primarily with the original embedding algorithm.

The use of crystallography, graphics, and quantitative structure-activity relationships in the analysis of the papain hydrolysis of X-phenyl hippurates

Abstract The effect of 3- and 4-monosubstitution and 3,5-disubstitution on the phenyl leaving group of the papain-catalyzed hydrolysis of 27 phenyl hippurates is reported. The Michaelis-Menten constant ( K m ) at 25.0 °C and pH 6.0 was determined for the substrates and, in addition, the first-order rate constant ( k ) for the uncatalyzed hydrolysis under the same conditions was measured. A quantitative structure-activity relationship was derived from the K m values. The conclusions from this analysis are in excellent agreement with the binding mode of the hippurates as shown by a molecular graphics analysis of the binding cavity which has been defined by X-ray crystallography.

CHUCKLES: A method for representing and searching peptide and peptoid sequences on both monomer and atomic levels

Dual representation of peptide and non-peptide structures in a chemical database as atomic-level molecular graphs and sequence strings permits chemical substructure and similarity searches as well as sequence-based substring and regular expression searches. CHUCKLES interconverts monomer-based sequences with SMILES, which represent atomic-level molecular graphs. Forward-translation maps peptide or other sequences into SMILES. Back-translation extracts monomer sequences from SMILES. This approach permits a generalized representation of monomers allowing user specification of any monomer. CHUCKLES allows mixing of atoms with user-defined monomer names; that is, monomer representation is consistent with SMILES notation. In addition, oligomer branching and cyclization are handled.

Nmr Structural Characterization of Oligo-N-Substituted Glycine Lead Compounds from a Combinatorial Library

Synthesis and screening of combinatorial librariesfor pharmaceutical lead discovery is a rapidlyexpanding field. Oligo-N-substituted glycines (NSGs)were one of the earliest sources of moleculardiversity in combinatorial libraries. In one of thefirst demonstrations of the power of combinatorialchemistry, two NSG trimers, CHIR-2279 and CHIR-4531,were identified as nM ligands for two 7-transmembraneG-protein-coupled receptors. The NMR characterizationof these two lead compounds was undertaken to verifycovalent connectivity and to determine solutionconformations, if any. The sequential chemical shiftassignments were performed using a new strategy forassigning 1H and 13C resonances of NSGs. The conformational preferences were then determined inboth an aqueous co-solvent system and an organicsolvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptidesdue to the tertiary amide, with both cis andtrans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279and CHIR-4531 have identical backbones and termini,and very similar side chains, they do not display thesame solution conformational characteristics.

CHORTLES: a method for representing oligomeric and template-based mixtures.

Screening mixtures of synthetic oligomers or fixed templates (e.g., rings) with varying substituents is increasingly the focus of drug discovery programs. CHORTLES is designed and implemented to facilitate representation, storage, and searching of oligomeric and template-based mixtures of any size. Building upon the CHUCKLES method of representing oligomers as both monomer-based sequences and all-atom structures, CHORTLES compactly represents a mixture without explicitly enumerating individual molecules. This method lends itself to a hierarchy relating mixtures to submixtures and individual compounds, as one finds when deconvoluting mixtures in drug lead discovery programs. In addition, we describe two methods of searching mixtures at the monomer level. We also present a simple pictorial representation for describing all components in a mixture, which becomes essential as the list of monomer names is expanded beyond common names (e.g., amino acids).

The combinatorial distance geometry method for the calculation of molecular conformation II. Sample problems and computational statistics

The performance of a branch and bound algorithm for molecular energy minimization is evaluated on a variety of test problems. Although not at present efficient enough for use in most practical situations, we show that it has distinct advantages over more conventional methods of global minimization. In addition, this study illustrates the technique on which the present algorithm is based, and the problems which must be overcome in developing an efficient algorithm based on similar principles.

Using Peptoid Libraries [Oligo N-Substituted Glycines] for Drug Discovery

Publisher Summary This chapter explores the use of peptoid libraries ‘oligo n -substituted glycines’ for drug discovery. A series of compounds for solid-phase synthesis have been prepared with functional groups similar to or identical to the natural amino acids. In general, either reductive amination, route A, or alkylation, route B, provide the necessary monomers. They are then incorporated into a growing peptide/peptoid chain using the activating agents BOP or PyBroP under conditions similar to the Merrifield approach to peptide synthesis. Yields and characteristics of the products are analogous to those of peptides. Oligomeric N substituted glycines (NSG) peptoids and peptide/peptoid chimeras have been prepared with activity in several different bioassays. Synthesis can also be accomplished using a different scheme. The NSG oligomer can be thought of as an alternating copolymer of acetate/amine units rather than an oligomer of NSG units. The submonomers can be sequentially reacted to give a growing peptoid chain identical to that synthesized by traditional Merrifield methods.