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Biomedical subjects

A R Leach

Publications and source records attributed to A R Leach.

10 recordsLinked to original sources
PubMed1994

The aggregation behaviour of two structurally isomeric glycolipids.

The two structurally isomeric glycolipids N-octyl-(1-hexadecylamido)-beta-D-glucopyranoside (Glc-N-[8/16]) and N-hexadecyl-(1-octylamido)-beta-D-glucopyranoside (Glc-N[16/8]) were synthesized. The lyotropic phase behaviour of these isomers was investigated in order to determine the extent to which the relative disposition of the alkyl chains with respect to the amide unit affects the aggregation properties of the amphiphiles. Both isomers exhibit lamellar and inverse topology cubic mesophases. The extent and polymorphism of the non-lamellar phases appear to be more pronounced in the Glc-N-[8/16] isomer relative to the Glc-N-[16/8] isomer. A molecular mechanics study was undertaken in an attempt to rationalize this behaviour.

Carbohydrate Sequence↗
PubMed1994

Ligand docking to proteins with discrete side-chain flexibility.

An algorithm is described that explores the conformational degrees of freedom of the amino acid side-chains and of the ligand when docking a putative ligand into a receptor site. For a given orientation of the ligand relative to the protein, the method can find the lowest energy combination of amino acid side-chains and ligand conformations as well as all other combinations in order of increasing energy within a specified energy cutoff. The amino acid side-chains and the ligand are restricted to discrete low-energy conformations, determined for the former by analysing high-resolution protein structures and in the latter case from a conformational analysis. Coupled to an algorithm for exploring the six degrees of orientational freedom of the ligand with respect to the receptor, the method can be used to perform conformationally flexible ligand docking. A combination of two search methods is employed to explore the conformational degrees of freedom: Dead End Elimination and the A* algorithm. When no ligand is present the approach can be used to predict the lowest energy combinations of side-chain conformations for a given protein backbone structure. The approach is employed to illustrate how such a procedure can be used to estimate the conformational entropy change that accompanies the formation of an intermolecular complex between a protein and a ligand and to demonstrate that the protein's conformational entropy may in some cases increase on binding the ligand. This is due to a modification of the protein's energy hypersurface that makes more conformational states accessible. Our results highlight the need for appropriate methods to estimate the strength of binding.

Algorithms↗
PubMed1994

Current methods for site-directed structure generation.

There has been a rapid growth of interest in techniques for site-directed drug design, fueled by the increasing availability of structural models of proteins of therapeutic importance, and by studies reported in the literature showing that potent chemical leads can be obtained by these techniques. Structure generation programs offer the prospect of discovering highly original lead structures from novel chemical families. Due to the fact that this technique is more-or-less still in its infancy, there are no case studies available that demonstrate the use of structure generation programs for site-directed drug design. Such programs were first proposed in 1986, and became commercially available in early 1992. They have shown their ability to reproduce, or suggest reasonable alternatives for, ligands in well-defined binding sites. This brief review will discuss the recent advances that have been made in the field of site-directed structure generation.

Algorithms↗
PubMed1994

Automated molecular design: a new fragment-joining algorithm.

A popular first step in the problem of structure-based, 'de novo' molecule design is to identify regions where specific functional groups or chemical entities would be expected to interact strongly. When the three-dimensional structure of the receptor is not available, it may be possible to derive a pharmacophore giving the three-dimensional relationships between such chemical groups. The task then is to design synthetically feasible molecules which not only contain the required groups, but which can also position them in the desired relative orientation. One way to do this is to first link the groups using an acyclic chain. We have investigated the application of the 'tweak' algorithm [Shenkin, P.S. et al., Biopolymers, 26 (1987) 2053] for generating families of acyclic linkers. These linking structures can subsequently be 'braced' using a ring-joining algorithm [Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233], giving rise to an even wider variety of molecular skeletons for further studies.

Algorithms↗
PubMed1993

Constitutional, configurational and conformational analysis of transition metal coordination complexes.

A computational approach to conformational analysis is applied to the study of transition metal coordination complexes. The method provides a means of rapidly exploring conformational space without any inherent reliance on energy calculations and is therefore applicable to a wide variety of systems. It has been incorporated into an algorithm which explores the constitutional, configurational and conformational degrees of freedom for a metal ion and a number of potential ligands. The program determines which of the possible coordination complex products could form stable conformations and can therefore be used to rationalise the products obtained from the mixture. The method is illustrated using two cases: the cobalt(III)-triethylenetetramine-glycine system and complexes of diindolopyridine derivatives.

Algorithms↗
PubMed1992

Enantioselective N-oxygenation of chlorpheniramine by the flavin-containing monooxygenase from hog liver.

1. The metabolism of racemic, (D)- and (L)-chlorpheniramine, a widely used antihistamine, was studied in microsomes and with highly purified flavin-containing monooxygenase from hog liver. 2. Although some N-demethylation was observed, the major metabolite of chlorpheniramine in hog liver microsomes was the aliphatic nitrogen N-oxide. Chlorpheniramine was extensively N-oxygenated by the highly purified flavin-containing monooxygenase from hog liver. 3. N-Oxygenation of chlorpheniramine in both microsomes and highly purified flavin-containing monooxygenase from hog liver was enantioselective. The Km for (D)-chlorpheniramine N-oxygenation was markedly lower than that for (L)-chlorpheniramine. 4. Molecular modelling studies were performed to investigate the nature of the substrate binding region.

Animals↗
PubMed1990

Automated conformational analysis: algorithms for the efficient construction of low-energy conformations.

The method of constructing low-energy conformations using template joining can provide an efficient means of searching the conformational space of molecules. The simplest algorithm to perform this task would construct each potential conformation from scratch. However, new algorithms, some of which use techniques from Artificial Intelligence, have been developed which can greatly improve the efficiency of this approach.

Algorithms↗
PubMed1990

Automated conformational analysis and structure generation: algorithms for molecular perception.

Many methodologies for performing automated conformational analysis require some means of "perceiving" a molecule to determine features of interest. Algorithms for finding rings, bond orders, and stereocenters and detecting the presence of substructural fragments have been developed. These algorithms are described, emphasizing their importance in conformational analysis.

Artificial Intelligence↗
PubMed1987

WIZARD: AI in conformational analysis.

A program which utilizes the techniques of Artificial Intelligence and Expert Systems to solve problems in the area of Conformational Analysis is described. The program searches conformational space in a systematic fashion, based on the technique known as heuristic state-space search. The program proceeds by recognizing conformational units, assigning one or more conformational templates to each unit, and joining them to form conformational suggestions. These suggestions are criticized to discover logical inconsistencies, and any resulting stresses are resolved. The resulting conformational suggestions are sometimes accurate enough for immediate use, or may be further refined by a numerical program. The latter combination is shown to be quite efficient compared to purely numerical conformational search techniques.

Artificial Intelligence↗