Biomedical subjects

P M Dean

Publications and source records attributed to P M Dean.

At least 19 recordsLinked to original sources

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↗

PubMed1995

The atom assignment problem in automated de novo drug design. 2. A method for molecular graph and fragment perception.

If atom assignment onto 3D molecular graphs is to be optimized, an efficient scheme for placement must be developed. The strategy adopted in this paper is to analyze the molecular graphs in terms of cyclical and non-cyclical nodes; the latter are further divided into terminal and non-terminal nodes. Molecular fragments, from a fragments database, are described in a similar way. A canonical numbering scheme for the fragments and the local subgraph of the molecular graph enables fragments to be placed efficiently onto the molecular graph. Further optimization is achieved by placing similar fragments into bins using a hashing scheme based on the canonical numbering. The graph perception algorithm is illustrated in detail.

Algorithms↗

PubMed1995

The atom assignment problem in automated de novo drug design. 3. Algorithms for optimization of fragment placement onto 3D molecular graphs.

Atom assignment onto 3D molecular graphs is a combinatoric problem in discrete space. If atoms are to be placed efficiently on molecular graphs produced in drug binding sites, the assignment must be optimized. An algorithm, based on simulated annealing, is presented for efficient optimization of fragment placement. Extensive tests of the method have been performed on five ligands taken from the Protein Data Bank. The algorithm is presented with the ligand graph and the electrostatic potential as input. Self placement of molecular fragments was monitored as an objective test. A hydrogen-bond option was also included, to enable the user to highlight specific needs. The algorithm performed well in the optimization, with successful replications. In some cases, a modification was necessary to reduce the tendency to give multiple halogenated structures. This optimization procedure should prove useful for automated de novo drug design.

Adenosine Monophosphate↗

PubMed1994

Recent advances in drug design methods: where will they lead?

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so-called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non-peptide scaffolds.

Drug Design↗

PubMed1994

Electrostatic complementarity between proteins and ligands. 1. Charge disposition, dielectric and interface effects.

Electrostatic interactions have always been considered an important factor governing ligand-receptor interactions. Previous work in this field has established the existence of electrostatic complementarity between the ligand and its receptor site. However, this property has not been treated rigorously, and the description remains largely qualitative. In this work, 34 data sets of high quality were chosen from the Brookhaven Protein Databank. The electrostatic complementary has been calculated between the surface potentials; complementarity is absent between adjacent or neighbouring atoms of the ligand and the receptor. There is little difference between complementarities on the total ligand surface and the interfacial region. Altering the homogeneous dielectric to distance-dependent dielectrics reduces the complementarity slightly, but does not affect the pattern of complementarity.

Amino Acid Sequence↗

PubMed1994

Electrostatic complementarity between proteins and ligands. 2. Ligand moieties.

Drug design strategies consider factors governing intermolecular interactions to build up putative ligands. In many strategies, the ligand is constructed using fragments which are placed in the site sequentially. The optimization is then performed with each fragment. We would like to examine if this optimization strategy could generate ligands with optimal electrostatic interactions. The electrostatic complementarities between constituent moieties and the receptor site have been calculated. The whole-ligand complementarity does not appear to be the mathematical mean of the individual complementarities, nor have we found a simple relationship between the moiety and whole-ligand complementarities. The results demonstrate clearly that, using a simple model, it is very difficult to predict the electrostatic potential complementarity of the whole ligand from the complementarities of its constituent chemical moieties. This means that ligand design strategies must optimize the electrostatic complementarity globally, and not moiety by moiety.

4-Hydroxybenzoate-3-Monooxygenase↗