Biomedical subjects

P M Dean

Publications and source records attributed to P M Dean.

At least 19 recordsLinked to original sources

PubMed2006

The impact of epilepsy surgery on quality of life in children.

OBJECTIVE: To determine if epilepsy surgery is effective in improving the quality of life (QOL) of children with intractable seizures using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). METHODS: The authors conducted a prospective study of the families of 35 children with intractable epilepsy who underwent epilepsy surgery. Parents completed the QOLCE preoperatively and again 6 to 18 months after surgery. At both assessment dates parents indicated the severity of their child's seizures during the past 6 months and the frequency of their child's seizures during the past 4 weeks on Likert-type scales. Children were split into two groups according to surgery outcome: seizure free vs persistent seizures. Statistical analyses were conducted to determine if children rendered seizure free showed a greater improvement in QOL compared to those with persistent seizures postoperatively. RESULTS: Greater improvement in QOL was documented for children rendered seizure free vs children with persistent seizures. This was significant for the overall QOLCE QOL score and subscales assessing cognitive, social, emotional, behavioral, and physical domains of life. CONCLUSIONS: Epilepsy surgery improves the quality of life of children rendered seizure free. Families can be counseled preoperatively of the potential benefits of surgery beyond seizure reduction.

Adolescent↗

PubMed2001

Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE.

New molecular modeling tools were developed to construct a qualitative pharmacophore model for histamine H3 receptor antagonists. The program SLATE superposes ligands assuming optimum hydrogen bond geometry. One or two ligands are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible H3 antagonists. In the derived model, four hydrogen-bonding site points and two hydrophobic pockets available for binding antagonists are revealed. The model results in a better understanding of the structure-activity relationships of H3 antagonists. To validate the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and the two hydrophobic pockets simultaneously. These ligands have high H3 receptor affinity, thereby illustrating how the model can be used in the design of new classes of H3 antagonists.

Animals↗

PubMed2001

Industrial-scale, genomics-based drug design and discovery.

The demands on drug discovery organizations have increased dramatically in recent years, partly because of the need to identify novel targets that are both relevant to disease and chemically tractable. This is leading to an industrial approach to traditional biology and chemistry, inspired in part by the revolution in genomics. The purpose of this article is to highlight the flow of investigation from gene sequence of potential therapeutic targets, through mRNA and protein expression, to protein structure and drug design. To deal with this scale of activity, many commercial and public organizations have been established and some of the key players will be listed in this article.

Drug Design↗

PubMed2001

SLATE: a method for the superposition of flexible ligands.

A novel program for the superposition of flexible molecules, SLATE, is presented. It uses simulated annealing to minimise the difference between the distance matrices calculated from the hydrogen-bonding and aromaticring properties of two ligands. A method for generating a molecular stack using multiple pairwise matches is illustrated. These stacks are used by the program DOH to predict the relative positions of receptor atoms that could form hydrogen bonds to two or more ligands in the dataset. The methodology has been applied to ligands binding to dihydrofolate reductase, thermolysin. H3 histamine receptors, alpha2 adrenoceptors and 5-HT1D receptors. When there are sufficient numbers and diversity of molecules in the dataset, the prediction of receptor-atom positions is applicable to compound design.

Folic Acid↗

PubMed2000

Recent advances in structure-based rational drug design.

Two approaches to structure-based drug design, that is, the docking of known compounds into a target protein and molecular assembly in situ, are seen to be merging technologies. The need for structural information about drug-protein complexes is now fundamental for drug discovery.

Animals↗

PubMed1999

Design criteria for molecular mimics of fragments of the beta-turn. 2. C alpha-C beta bond vector analysis.

In a previous paper, we have shown the utility of cluster analysis for identifying patterns in the way the C alpha atoms of fragments of the beta-turn are distributed in three dimensions. This work has been extended to the C alpha-C beta bond vectors of 2- and 3-side-chain fragments. Again, distinct patterns emerge and 10 and 12 classes of vector orientation have been identified for the 2- and 3-vector problem, respectively. These clusters of vector distribution provide an optimal reduced set of design criteria for the de novo generation of novel peptidomimetics for fragments of the beta-turn.

Carbon↗

PubMed1999

Design criteria for molecular mimics of fragments of the beta-turn. 1. C alpha atom analysis.

Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the beta-turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the beta-turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different beta-turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C alpha atoms about the various fragments of the beta-turn. Recombination of the observed patterns provides a general model for the beta-turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases.

Carbon↗

PubMed1998

A branch-and-bound method for optimal atom-type assignment in de novo ligand design.

This paper investigates a computational procedure for the determination of the atom types on the vertices of a molecular skeleton to optimize interaction with the receptor site whilst maintaining a synthetically reasonable structure. The connectivity of the skeleton is analysed and appropriate atom types are compiled for each vertex. Receptor ionization and conformational states are generated by varying the positions of hydrogen atoms and electron lone pairs in the carboxyl, rotatable hydroxyl and amino groups. The structure is divided into small non-overlapping substructures. Atom types are assigned exhaustively onto each of the substructures using a depth-first search method; chemical rules are applied to reject unacceptable atom combinations early on. An empirical interaction score is calculated and the representatives of each partial structure are stored in ascending order according to their scores. The branch-and-bound procedure is then used to find the structures with the lowest scores. The method is illustrated using five protein-ligand complexes.

Algorithms↗

PubMed1997

An automated method for predicting the positions of hydrogen-bonding atoms in binding sites.

Hydrogen bonds are the most specific, and therefore predictable of the intermolecular interactions involved in ligand-protein binding. Given the structure of a molecule, it is possible to estimate the positions at which complementary hydrogen-bonding atoms could be found. Crystal-survey data are used in the design of a program, HBMAP, that generates a hydrogen-bond map for any given ligand, which contains all the feasible positions at which a complementary atom could be found. On superposition of ligands, the overlapping regions of their maps represent positions of receptor atoms to which each molecule can bind. The certainty of these positions is increased by the incorporation of a larger number and diversity of molecules. In this work, superposition is achieved using the program HBMATCH, which uses simulated annealing to generate the correspondence between points from the hydrogen-bonding maps of the two molecules. Equivalent matches are distinguished on the basis of their steric similarity. The strategy is tested on a number of ligands for which ligand-protein complexes have been solved crystallographically, which allows validation of the techniques. The receptor atom positions of thermolysin are successfully predicted when the correct superposition is obtained.

Antithrombins↗

PubMed1997

Evaluation of a method for controlling molecular scaffold diversity in de novo ligand design.

We describe an algorithm for the automated generation of molecular structures subject to geometric and connectivity constraints. The method relies on simulated annealing and simplex optimization of a penalty function that contains a variety of conditions and can be useful in structure-based drug design projects. The procedure controls the diversity and complexity of the generated molecules. Structure selection filters are an integral part and drive the algorithm. Several procedures have been developed to achieve reliable control. A number of template sets can be defined and combined to control the range of molecules which are searched. Ring systems are predefined. Normally, the ring-system complexity is on of the most elusive and difficult factors to control when fusion-, bridge- and spiro-structures are built by joining templates. Here this is not an issue; the decision about which systems are acceptable, and which are not, is made before the run is initiated. Queries for inclusion and exclusion spheres are incorporated into the objective function, and, by using a flexible notation, the structure generation can be directed and more focused. Simulated annealing is a reliable optimizer and converges asymptotically to the global minimum. The objective functions used here are degenerate, so it is likely that each run will produce a different set of good solutions.

Algorithms↗

PubMed1996

Three-dimensional hydrogen-bond geometry and probability information from a crystal survey.

An extensive crystal survey of the Cambridge Structural Database has been carried out to provide hydrogen-bond data for use in drug-design strategies. Previous crystal surveys have generated 1D frequency distributions of hydrogen-bond distances and angles, which are not sufficient to model the hydrogen bond as a ligand-receptor interaction. For each hydrogen-bonding group of interest to the drug designer, geometric hydrogen-bond criteria have been derived. The 3D distribution of complementary atoms about each hydrogen-bonding group has been ascertained by dividing the space about each group into bins of equal volume and counting the number of observed hydrogen-bonding contacts in each bin. Finally, the propensity of each group to form a hydrogen bond has been calculated. Together, these data can be used to predict the potential site points with which a ligand could interact and therefore could be used in molecular-similarity studies, pharmacophore query searching of databases, or de novo design algorithms.

Crystallography, X-Ray↗

PubMed1995

The atom assignment problem in automated de novo drug design. 4. Tests for site-directed fragment placement based on molecular complementarity.

Three previous papers in this series have outlined an optimization method for atom assignment in drug design using fragment placement. In this paper the procedure is rigorously tested on a selection of five ligand-protein co-crystals. The algorithm is presented with the molecular graph of the ligand, and the electrostatic/hydrophobic potential of the site, with the aim of creating a placement on the molecular graph which is as electrostatically complementary or hydrophobically similar to the site as possible. Various designer options were tested, including, where appropriate, hydrogen bonding and a restricted number of halogens. In most cases, the placement obtained was at least as good as the native ligand, if not significantly better.

4-Hydroxybenzoate-3-Monooxygenase↗

PubMed1995

The atom assignment problem in automated de novo drug design. 5. Tests for envelope-directed fragment placement based on molecular similarity.

The fragment placement method has been successfully extended to the problem of envelope-directed design. The atom assignment paradigm was based on molecular similarity between two molecular structures. A composite supersurface is defined to form the surface onto which the molecular fields are projected. The assignment process is then determined by using molecular similarity in the objective function to be optimized. In principle, this procedure is closely similar to that outlined in the previous paper for site-directed design. The rationale has been extensively tested on two benzodiazepine antagonists believed to bind to the same site.

Binding Sites↗

PubMed1995

Molecular surface-volume and property matching to superpose flexible dissimilar molecules.

Steric complementarity is a prerequisite for ligand-receptor recognition; this implies that drugs with a common receptor binding site should possess sterically similar binding surfaces. This principle is used as the basis for an automatic and unbiased method that superposes molecules. One molecule is rotated and translated to maximize the overlap between the two molecular surface volumes. A fast grid-based method is used to determine the extent of this overlap, and this is optimized using simulated annealing. Matches with high steric similarity scores are then sorted on the basis of both hydrogen-bond and electrostatic similarity between the matched molecules. Flexible molecules are treated as a set of rigid representative conformers. The algorithm has correctly predicted superpositions between a number of paris of molecules, according to crystallographic data from ligands that have been co-crystallized at common enzyme binding sites.

Allosteric Site↗

PubMed1995

Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions.

Water is known to play an important role in the recognition and stabilization of the interaction between a ligand and its site. This has important implications for drug design. Analyses of 19 high-resolution crystal structures of protein-ligand complexes reveal the multiple hydrogen-bonding feature of water molecules mediating protein-ligand interactions. Most of the water molecules (nearly 80%) involved in bridging the protein and the ligand can make three or more hydrogen bonds when distance and bond angles are used as criteria to define hydrogen-bonding interactions. Isotropic B-factors have been used to take into account the mobility of water molecules. The water molecules at binding sites bridge the protein and ligand, and interact with other water molecules to form a complex network of interconnecting hydrogen bonds. Some water molecules at the site do not directly bridge between the protein and the ligand, but may contribute indirectly to the stability of the complex by holding bridging water molecules in the right position through a network of hydrogen bonds. These water networks are probably crucial for the stability of the protein-ligand complex and are important for any site-directed drug design strategies.

Animals↗

PubMed1995

Hydration in drug design. 2. Influence of local site surface shape on water binding.

If water molecules are strongly bound at a protein-ligand interface, they are unlikely to be displaced during ligand binding. Such water molecules can change the shape of the ligand binding site and thus affect strategies for drug design. To understand the nature of water binding, and factors influencing it, water molecules at the ligand binding sites of 26 high-resolution protein-ligand complexes have been examined here. Water molecules bound in deep grooves and cavities between the protein and the ligand are located in the indentations on the protein-site surface, but not in the indentations on the ligand surface. The majority of the water molecules bound in deep indentations on the protein-site surface make multiple polar contacts with the protein surface. This may indicate a strong binding of water molecules in deep indentations on protein-site surfaces. The local shape of the site surface may influence the binding of water molecules that mediate protein-ligand interactions.

Animals↗

PubMed1995

Hydration in drug design. 3. Conserved water molecules at the ligand-binding sites of homologous proteins.

Water molecules are known to play an important rôle in mediating protein-ligand interactions. If water molecules are conserved at the ligand-binding sites of homologous proteins, such a finding may suggest the structural importance of water molecules in ligand binding. Structurally conserved water molecules change the conventional definition of 'binding sites' by changing the shape and complementarity of these sites. Such conserved water molecules can be important for site-directed ligand/drug design. Therefore, five different sets of homologous protein/protein-ligand complexes have been examined to identify the conserved water molecules at the ligand-binding sites. Our analysis reveals that there are as many as 16 conserved water molecules at the FAD binding site of glutathione reductase between the crystal structures obtained from human and E. coli. In the remaining four sets of high-resolution crystal structures, 2-4 water molecules have been found to be conserved at the ligand-binding sites. The majority of these conserved water molecules are either bound in deep grooves at the protein-ligand interface or completely buried in cavities between the protein and the ligand. All these water molecules, conserved between the protein/protein-ligand complexes from different species, have identical or similar apolar and polar interactions in a given set. The site residues interacting with the conserved water molecules at the ligand-binding sites have been found to be highly conserved among proteins from different species; they are more conserved compared to the other site residues interacting with the ligand. These water molecules, in general, make multiple polar contacts with protein-site residues.

Animals↗

PubMed1995

The atom assignment problem in automated de novo drug design. 1. Transferability of molecular fragment properties.

This paper is the first of a series which examines the problems of atom assignment in automated de novo drug design. In subsequent papers, a combinatoric optimization method for fragment placement onto 3D molecular graphs is provided. Molecules are built from molecular graphs by placing fragments onto the graph. Here we examine the transferability of atomic residual charge, by fragment placement, with respect to the electrostatic potential. This transferability has been tested on 478 molecular structures extracted from the Cambridge Structural Database. The correlation found between the electrostatic potential computed from composite fragments and that computed for the whole molecule was encouraging, except for extended conjugated systems.

Computer Simulation↗