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Biomedical subjects

P M Dean

Publications and source records attributed to P M Dean.

At least 19 recordsLinked to original sources
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↗
PubMed1989

Automated site-directed drug design: the formation of molecular templates in primary structure generation.

In this paper the spacer skeleton concept is used to produce molecular graphs of putative ligands for binding sites. The skeletons are transformed into molecular templates within the constraints of the accessible surface of the ligand-binding site. A distance-matrix method is used to compare ligand points with vertices of the spacer skeleton through a permutation of all possible correspondences. A tolerance parameter is used to screen for poor matches. As a result, a small number of matched vertices and ligand points are produced. These are fitted into the site by a constrained optimization routine using an analytical function. Ligand points fall within the site and are optimally positioned adjacent to the corresponding site points; other vertices of the spacer skeleton lying beneath the accessible surface of the site are clipped off. A molecular template is thereby formed with its vertices linked to the ligand points. The final step is to verify that the bonding integrity of the skeleton remains. The computational methods outlined in this paper have been tested at two binding sites: the pteridine binding site in dihydrofolate reductase and the amidinophenylpyruvate site of trypsin. Molecular graphs for both sites were generated automatically; they showed strong similarity to those of the natural ligands.

Drug Design↗
PubMed1989

Toffee clearance and lingual sensory and motor activities in normal children and in children with articulation problems of speech.

The rate at which a standardized mouthful of toffee containing technetium (99mTc) tin colloid was cleared from the mouth during and after chewing was measured by counting the residual radioactivity in the mouth at short time intervals by external gamma counting. The clearance curve was resolved into three phases for each subject--chewing time (1), which coincided with the time to reach 10% of the initial counting rate, scavenging time (2), and a final slow diffusion phase (3). Although the mean chewing time was only 1.9 min, the technique allowed the pattern of clearance during this phase to be assessed for each of 10 normal children (mean age 11.1 yr) and 7 children (mean age 11.0 yr) diagnosed as having delayed articulation. Two measurements of sensory and motor functions of the tongue were made on the same subjects. These measurements were of oral stereognosis and tongue-tip manipulation. Within the control group, only the correlation between stereognosis error scores and the duration of phase 1 or phases 1 and 2 combined was statistically significant. The mean stereognosis and tongue manipulation scores were significantly lower in the poor articulation group than in normal children but, with one notable exception, the clearance curves were similar.

Adolescent↗
PubMed1985

The search for functional correspondences in molecular structure between two dissimilar molecules.

Where structural similarities between molecular ligands are suspected in competitive binding, these similarities may be represented by a set of correspondences between analogous ligand points in the two molecules. This paper describes an algorithm which searches through all possible sets of this form, to find the one which gives the best geometric fit between matched points. Two parameters are supplied to the algorithm, giving the number of correspondences required and the tolerance permitted in the fit. A tree-search technique is used, and methods are described which prune the tree and thus limit the search. The marine neurotoxins, saxitoxin and tetrodotoxin, are used to test a computer implementation of the procedure.

Binding, Competitive↗
PubMed1980

Electrostatic components of drug-receptor recognition. I. Structural and sequence analogues of DNA polynucleotides.

The electrostatic fields associated with the important biological receptor DNA have been studied by means of stereoscopic displays to investigate drug-receptor recognition processes. This revealed great differences between A- and B-type structures and enabled significant nucleotide sequence effects to be detected for the latter helix. These variations were further investigated by topological analysis of the surface potential in the two grooves of the B-DNA duplex at different radii from the helix axis. This made it possible to characterize the potential surface and to allocate curvature changes to specific atomic groupings. A general finding was that larger potential fields were found in the space encompassed by the narrow groove with strong potential gradients from the ends of the helix to the centre in both grooves. This gradient may provide a motive force for translating small molecules on the surface of a polynucleotide.

DNA↗
PubMed1980

Electrostatic components of drug-receptor recognition. II. The DNA-binding antibiotic actinomycin.

The semiempirical molecular orbital method PCILO has been used to study the electronic charge distribution and conformation of the antibiotic actinomycin. Molecular electrostatic potential fields have been constructed in three-dimensional space round the molecule and displayed stereoscopically together with contour maps in the orthogonal planes relative to that of the chromophore. It was found that the drug has a considerable dipole moment and that the electrostatic fields can be separated into two large regions; an area of positive potential surrounds the chromophore and one of negative potential is directed away from the peptide rings. In this and the preceding paper these observations are discussed with respect to drug-receptor recognition phenomena. Pattern-matching of complementary electrostatic fields between the drug and polynucleotide receptor can be discerned.

Chemical Phenomena↗
PubMed1976

The kinetics of beta-granule formation: a morphometric study.

The rate of formation of beta-granules in mouse islet cells has been studied by morphometry using experimental conditions in which insulin secretion is known to be blocked. The number of beta-granules in a cell is increased by 120%, 45 minutes after a continued glucose stimulus of 16.7 mM. The implications of the results are discussed with respect to the construction of kinetic models for the secretion of insulin by exocytosis.

Animals↗