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Biomedical subjects

D R Westhead

Publications and source records attributed to D R Westhead.

15 recordsLinked to original sources
PubMed1999

Protein structural topology: Automated analysis and diagrammatic representation.

The topology of a protein structure is a highly simplified description of its fold including only the sequence of secondary structure elements, and their relative spatial positions and approximate orientations. This information can be embodied in a two-dimensional diagram of protein topology, called a TOPS cartoon. These cartoons are useful for the understanding of particular folds and making comparisons between folds. Here we describe a new algorithm for the production of TOPS cartoons, which is more robust than those previously available, and has a much higher success rate. This algorithm has been used to produce a database of protein topology cartoons that covers most of the data bank of known protein structures.

Algorithms↗
PubMed1998

Flexible docking using Tabu search and an empirical estimate of binding affinity.

This article describes the implementation of a new docking approach. The method uses a Tabu search methodology to dock flexibly ligand molecules into rigid receptor structures. It uses an empirical objective function with a small number of physically based terms derived from fitting experimental binding affinities for crystallographic complexes. This means that docking energies produced by the searching algorithm provide direct estimates of the binding affinities of the ligands. The method has been tested on 50 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. All water molecules are removed from the structures and ligand molecules are minimized in vacuo before docking. The lowest energy geometry produced by the docking protocol is within 1.5 A root-mean square of the experimental binding mode for 86% of the complexes. The lowest energies produced by the docking are in fair agreement with the known free energies of binding for the ligands.

Algorithms↗
PubMed1998

New tools and resources for analysing protein structures and their interactions.

The determination of protein structures has furthered our understanding of how various proteins perform their functions. With the large number of structures currently available in the PDB, it is necessary to be able to easily study these proteins in detail. Here new software tools are presented which aim to facilitate this analysis; these include the PDBsum WWW site which provides a summary description of all PDB entries, the programs TOPS and NUCPLOT to plot schematic diagrams representing protein topology and DNA-binding interactions, SAS a WWW-based sequence-analysis tool incorporating structural data, and WWW servers for the analysis of protein-protein interfaces and analyses of over 300 haem-binding proteins.

Amino Acid Sequence↗
PubMed1998

Protein structure prediction.

Genome sequencing projects continue to provide a flood of new protein sequences, and prediction methods remain an important means of adding structural information. Recently, there have been advances in secondary structure prediction, which feed, in turn, into improved fold recognition algorithms. Finally, there have been technical improvements in comparative modelling, and studies of the expected accuracy of three-dimensional structural models built by this method.

Journal Article↗
PubMed1997

A comparison of heuristic search algorithms for molecular docking.

This paper describes the implementation and comparison of four heuristic search algorithms (genetic algorithm, evolutionary programming, simulated annealing and tabu search) and a random search procedure for flexible molecular docking. To our knowledge, this is the first application of the tabu search algorithm in this area. The algorithms are compared using a recently described fast molecular recognition potential function and a diverse set of five protein-ligand systems. Statistical analysis of the results indicates that overall the genetic algorithm performs best in terms of the median energy of the solutions located. However, tabu search shows a better performance in terms of locating solutions close to the crystallographic ligand conformation. These results suggest that a hybrid search algorithm may give superior results to any of the algorithms alone.

Algorithms↗
PubMed1997

PRO_SELECT: combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology.

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritized for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

Computer-Aided Design↗
PubMed1996

Active-site-directed 3D database searching: pharmacophore extraction and validation of hits.

Two new computational tools, PRO_PHARMEX and PRO_SCOPE, for use in active-site-directed searching of 3D databases are described. PRO_PHARMEX is a flexible, graphics-based program facilitating the extraction of pharmacophores from the active site of a target macromolecule. These pharmacophores can then be used to search a variety of databases for novel lead compounds. Such searches can often generate many 'hits' of varying quality. To aid the user in setting priorities for purchase, synthesis or testing, PRO_SCOPE can be used to dock molecules rapidly back into the active site and to assign them a score using an empirical scoring function correlated to the free energy of binding. To illustrate how these tools can add value to existing 3D database software, their use in the design of novel thrombin inhibitors is described.

Binding Sites↗
PubMed1996

Evolutionary algorithms in computer-aided molecular design.

In recent years, search and optimisation algorithms inspired by evolutionary processes have been applied with marked success to a wide variety of problems in diverse fields of study. In this review, we survey the growing application of these 'evolutionary algorithms' in one such area: computer-aided molecular design. In the course of the review, we seek to summarise the work to date and to indicate where evolutionary algorithms have met with success and where they have not fared so well. In addition to this, we also attempt to discern some future trends in both the basic research concerning these algorithms and their application to the elucidation, design and modelling of chemical and biochemical structures.

Algorithms↗
PubMed1995

PRO-LIGAND: an approach to de novo molecular design. 1. Application to the design of organic molecules.

An approach to de novo molecular design, PRO-LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies--placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO-LIGAND's efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.

Computer Simulation↗
PubMed1995

PRO-LIGAND: an approach to de novo molecular design. 3. A genetic algorithm for structure refinement.

Recently, the development of computer programs which permit the de novo design of molecular structures satisfying a set of steric and chemical constraints has become a burgeoning area of research and many operational systems have been reported in the literature. Experience with PRO-LIGAND-the de novo design methodology embodied in our in-house molecular design and simulation system PRO-METHEUS-has suggested that the addition of a genetic algorithm (GA) structure refinement procedure can 'add value' to an already useful tool. Starting with the set of designed molecules as an initial population, the GA can combine features from both high- and low-scoring structures and, over a number of generations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a procedure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.

Algorithms↗
PubMed1995

PRO_LIGAND: an approach to de novo molecular design. 4. Application to the design of peptides.

In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disadvantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.

Amino Acid Sequence↗
PubMed1995

Protein fold recognition by threading: comparison of algorithms and analysis of results.

Optimal sequence threading can be used to recognize members of a library of protein folds which are closely related in 3-D structure to the native fold of an input test sequence, even when the test sequence is not significantly homologous to the sequence of any member of the fold library. The methods provide an alignment between the residues of the test sequence and the residue positions in a template fold. This alignment optimizes a score function, and the predicted fold is the highest scoring member of the library of folds. Most score functions contain a pairwise interaction energy term. This, coupled with the need to introduce gaps into the alignment, means that the optimization problem is NP hard. We report a comparison between two heuristic optimization algorithms used in the literature, double dynamic programming and an iterative algorithm based on the so-called frozen approximation. These are compared in terms of both the ranking of likely folds and the quality of the alignment produced.

Algorithms↗
PubMed1994

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

A physiologically based mathematical model of dermal absorption in man.

A sound understanding of the mechanisms determining percutaneous absorption is necessary for toxicological risk assessment of chemicals contacting the skin. As part of a programme investigating these mechanisms we have developed a physiologically based mathematical model. The structure of the model parallels the multi-layer structure of the skin, with separate surface, stratum corneum and viable tissue layers. It simulates the effects of partitioning and diffusive transport between the sub-layers, and metabolism in the viable epidermis. In addition the model describes removal processes on the surface of the skin, including the effects of washing and desquamation, and rubbing off onto clothing. This model is applied to data on the penetration of the herbicide fluazifop-butyl through human skin in vivo and in vitro. Part of this dataset is used to estimate unknown model parameter values and the remainder is used to provide a partial validation of the model. Only a small fraction of the applied dose was absorbed through the skin; most of it was removed by washing or onto clothing. The model provides a quantitative description of these loss processes on the skin surface.

Administration, Cutaneous↗