Search PubMed⌕ Search

Biomedical subjects

P M Dean

Publications and source records attributed to P M Dean.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1994

Electrostatic complementarity between proteins and ligands. 3. Structural basis.

Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of superposition. Example studies suggest that in many ligand-protein pairs, there exist principal formal charges on each molecule, largely responsible for the electrostatic potential complementarity observed. Electrostatic potential complementarity depends on the relative disposition of these principal charges and the ligand van der Waals surface. Simple mathematical models were constructed to predict the complementarity solely from structural considerations. The essential conditions for electrostatic potential complementarity were elucidated. These can be used in ligand design strategies to obtain an electrostatically optimal ligand.

Amino Acid Sequence↗
PubMed1993

An exploration of a novel strategy for superposing several flexible molecules.

This paper describes a computational strategy for the superposition of a set of flexible molecules. The combinatorial problems of searching conformational space and molecular matching are reduced drastically by the combined use of simulated annealing methods and cluster analysis. For each molecule, the global minimum of the conformational energy is determined by annealing and the search trajectory is retained in a history file. All the significantly different low-energy conformations are extracted by cluster analysis of data in the history file. Each pair of molecules, in each of their significantly different conformations, is then matched by simulated annealing, using the difference-distance matrix as the objective function. A set of match statistics is then obtained, from which the best match taken from all different conformations can be found. The molecules are then superposed either by reference to a base molecule or by a consensus method. This strategy ensures that as wide a range of conformations as possible is considered, but at the same time that the smallest number of significantly different conformations is used. The method has been tested on a set of six angiotensin II antagonists with between 7-11 rotatable bonds.

Algorithms↗
PubMed1992

Inhibition of alloxan-induced hyperglycaemia by compounds of similar molecular structure.

In this study we have shown that a range of compounds that are structurally similar to alloxan are able to protect mice against the diabetogenic effect of alloxan. The compounds include a group of five barbiturates, a group of five hydantoins, the methylxanthines caffeine and theophylline, the related compound uric acid, and ethosuximide. They were injected intraperitoneally prior to intravenous injection of alloxan, and blood glucose concentration was used as an index of alloxan toxicity. The salient structural feature possessed by all of these protective compounds is a pair of carbonyl oxygen atoms separated by a distance of 4.5 A and projecting from an approximately planar heterocyclic five- or six-membered ring; in all cases the carbonyl groups are separated by a ring nitrogen. We suggest that this feature is required for the protective effect of these compounds. In order to test further the requirement for two ring carbonyl groups, we also examined the effects of two compounds containing hydroxyl groups projecting from a six-membered ring, inositol and glucuronic acid. In agreement with previous studies on hexoses, we found that the effects of compounds such as these are unpredictable, with inositol protecting against alloxan toxicity but glucuronic acid not. We are unable to identify the critical difference in structure between these two compounds.

Allantoin↗
PubMed1992

Automated site-directed drug design: the generation of a basic set of fragments to be used for automated structure assembly.

If a method is to be developed to assemble putative ligand structures in site-directed drug design, from molecular graphs generated in the site, then basic building blocks are needed. Structure assembly is a combinatoric process that needs to be optimised if it is to be tractable. What has to be determined is whether small molecular fragments can have transferable properties from one molecule to another. In this paper we determine all possible combinations of 3-, 4- and 5-atom aliphatic fragments from a small set of atoms H, C, N, O, F or Cl. The frequency of occurrence of these candidate fragments is searched for in the Cambridge Structural Database. A similar analysis is performed on charged fragments. A more restricted search is carried out for P and S and aromatic structures. A basic set of fragments can be derived that have a significant frequency in known crystal structures. The transferability of fragment properties is discussed in subsequent papers.

Computer-Aided Design↗
PubMed1992

Automated site-directed drug design: an assessment of the transferability of atomic residual charges (CNDO) for molecular fragments.

In this paper a database of atomic residual charges has been constructed for all the molecular fragments defined previously in a combinatorial search of the Cambridge Structural Database. The charges generated for the atoms in each fragment are compared with charges calculated for whole molecules containing those fragments. The fragment atomic charges lie within 1 S.D. of the mean for 68%, and within 2 S.D. for 91%, of the atoms whose charges were computed for whole molecules. The actual charges on any atom are strongly influenced by the adjacent connected atoms. There is a large spread of atomic residual charge within the fragments database.

Computer-Aided Design↗
PubMed1991

Molecular structure matching by simulated annealing. III. The incorporation of null correspondences into the matching problem.

This paper extends an application of the method of simulated annealing for molecular matching so that the best common subsets of atom positions can be identified. Null correspondences are introduced into the difference distance matrix to enable poorly matched positions to be ignored in minimizing the objective function. The efficiency of the algorithm in finding correct subsets is rigorously tested.

Algorithms↗
PubMed1991

Molecular structure matching by simulated annealing. IV. Classification of atom correspondences in sets of dissimilar molecules.

A set of 6 molecules, active at the benzodiazepine GABAA site are matched pairwise with one member of the set in turn. Matchings are performed by simulated annealing using null correspondences to reject poorly matched atom positions. Cluster analysis is employed to identify molecular similarities after an optimal molecular superimposition has been discovered. A statistic for the compactness of clustered atom positions is suggested. The introduction of null correspondences causes the clusters of matched atoms to become more compact.

Benzodiazepines↗
PubMed1990

Molecular structure matching by simulated annealing. I. A comparison between different cooling schedules.

This paper outlines an application of the theory of simulated annealing to molecular matching problems. Three cooling schedules are examined: linear, exponential and dynamic cooling. The objective function is the sum of the elements of the difference distance matrix between the two molecules generated by continual reordering of one molecule. Extensive tests of the algorithms have been performed on random coordinate data together with two related protein structures. Combinatorial problems, inherent in the assignment of atom correspondences, are effectively overcome by simulated annealing. The algorithms outlined here can readily optimize molecular matching problems with 150 atoms.

Algorithms↗
PubMed1990

Molecular structure matching by simulated annealing. II. An exploration of the evolution of configuration landscape problems.

This paper considers some of the landscape problems encountered in matching molecules by simulated annealing. Although the method is in theory ergodic, the global minimum in the objective function is not always encountered. Factors inherent in the molecular data that lead the trajectory of the minimization away from its optimal route are analysed. Segments comprised of the C alpha atoms of dihydrofolate reductase are used as test data. The evolution of a reverse ordering landscape problem is examined in detail. Where such patterns in the data could lead to incorrect matches, the problem can in part be circumvented by assigning an initial random ordering to the molecules.

Algorithms↗
PubMed1989

Automated site-directed drug design: a general algorithm for knowledge acquisition about hydrogen-bonding regions at protein surfaces.

This is the first of four papers that begin to explore the possibility of automated site-directed drug design. A general outline is given of the logical steps involved in approaching the problem. The starting point is the process of knowledge acquisition about the site. An algorithm is described here for the construction of a map of hydrogen-bonding regions at protein surfaces directly from the Brookhaven Protein Data Bank coordinates. Hydrogen-bonding atoms are located, intramolecular bonds are searched for, hydrogen-bonding atoms at the surface are found and hydrogen-bonding regions are computed at the accessible surface. A grid is placed within each region discovered and the probability of hydrogen bonding at each grid point is computed. The output of the program is a map of hydrogen-bonding regions displayed within a user-defined window. This information can be used as part of a knowledge base for the automatic construction of novel ligands to fit specified binding sites.

Algorithms↗
PubMed1989

Automated site-directed drug design: the prediction and observation of ligand point positions at hydrogen-bonding regions on protein surfaces.

The HSITE program proposed in the previous paper was written to define putative ligand-point regions that could be found at protein surfaces. These regions would represent positions for hydrogen-bonding acceptor and donor atoms. In this paper the prediction of the location of these regions is compared with: (1) the position of the oxygen atoms of water molecules on the hydrated proteins myoglobin and plastocyanin; and (2) the position of hydrogen-bonded atoms in methotrexate and NADPH co-crystallized with dihydrofolate reductase, and in amidinophenyl-pyruvate co-crystallized with trypsin. The prediction of ligand-point regions is in agreement with the surveys of experimental data for water-molecule positions in protein crystals and with the positions of hydrogen-bonding atoms found in co-crystallized ligands.

Drug Design↗
PubMed1989

Automated site-directed drug design: the concept of spacer skeletons for primary structure generation.

This paper examines the problem of automated structure generation at specified binding sites. The objective is to obtain molecular graphs that span the binding site and incorporate predicted ligand points at their vertices. Three approaches are considered: brute-force techniques, subgraph addition and spacer skeletons. Spacer skeletons are assemblies of molecular subgraphs and are used to reduce the combinatorial problems of structure generation to a practicable level for future analysis. This description is restricted to structure generation in two dimensions. Assemblies of rings are examined for planarity by searching the Cambridge Structural Database. Appropriate spacer skeletons may then be fitted to arrays of site points.

Computer Simulation↗