Biomedical subjects
W G Richards
Publications and source records attributed to W G Richards.
Application of neural networks: quantitative structure-activity relationships of the derivatives of 2,4-diamino-5-(substituted-benzyl)pyrimidines as DHFR inhibitors.
A comparative study of quantitative structure-activity relationships involving diaminopyrimidines as DHFR inhibitors using regression analysis and the neural-network approach suggests that the neural network can outperform traditional methods. The technique permits the highlighting the functional form of those parameters which have an influence on the biological activity.
Similarity screening of molecular data sets.
Three-dimensional (3D)-database searches are now being widely applied to determine potential new active molecules. Many structural data sets obtained as a result of these searches are still large in size. In this paper we apply molecular similarity calculations as a rapid method to screen two such data sets. In the first investigation, synthetic candidates, produced as a result of a tendamistat beta-turn mimic search, were tested for their ability to imitate the beta-turn backbone. In the second study, structures extracted through a histamine pharmacophore query search were examined on the basis of their electronic similarity to histamine. Molecular similarity is shown to provide a rapid means of gaining insight into the composition of molecular data sets, with possible implications for future full 3D-database searches.
A molecular dynamics simulation of a polyamine-induced conformational change of DNA. A possible mechanism for the B to Z transition.
A 75ps molecular dynamics simulation has been performed on a fully solvated complex of spermine with the B DNA decamer (dGdC)5.(dGdC)5. The simulation indicates a possible mechanism by which polyamines might induce the formation of a left-handed helix, the B to Z transition. Spermine was initially located in the major groove, hydrogen bonded to the helix. During the simulation the ligand migrates deeper into the DNA, maintaining strong hydrogen bonding to the central guanine bases and destroying the Watson-Crick base pairing with their respective cytosines. Significant rotation of these and other cytosine bases was observed, in part due to interactions of the helix with the aminopropyl chains of spermine. An intermediate BII conformation might be of importance in this process.
Activity of spinal trigeminal pars oralis and adjacent reticular formation units during differential conditioning of the rabbit nictitating membrane response.
Spinal trigeminal nucleus pars oralis (SpoV) is anatomically linked to brain circuitry thought to subserve unconditioned and conditioned nictitating membrane responses in rabbit. Single-unit recording from SpoV and adjacent reticular formation obtained during conditioning from awake, behaving animals revealed modulation of unit firing related to CS, US, and CR occurrence. SpoV participates directly in the unconditioned response and probably relays US information to other brain areas subserving conditioning. The presence of CR-related activity suggests that SpoV may participate in the CR motor output pathway, and may also provide CR-related information to cerebellum. Sensory convergence and CR-related activity in reticular formation mark this structure as a candidate locus of primary neuronal plasticity in this example of conditioning.
Electron transport in cytochromes P-450 by covalent switching.
The mechanism of electron transfer in cytochrome P-450cam is presented in terms of a covalent switching mechanism. We present a model of putidaredoxin built by homology, which helps explain protein-protein interactions. The mechanism is general enough to account for the genetic variations found in the superfamily of cytochromes P-450. The detail should assist in the design of novel P-450 inhibitors and may have wider implications. The sequence analysis supports our protein model, and highlights the role of cystein and aromatic residues in electron-transport mechanisms. Eukaryotic cytochromes P-450 appear to have evolved their own intramolecular tryptophan electron-transfer mediator, unlike prokaryotic P. putida P-450cam, which still relies upon the C-terminal tryptophan of its attendant electron-transport protein, putidaredoxin. On this basis our protein model is capable of rationalizing the transfer of electrons from NADH to the active site of P-450. At the electronic level the covalent switching that transfers pairs of electrons not only provides a plausible mechanism, but may also have ramifications in a wider context.
A molecular mechanics study of spermine complexation to DNA: a new model for spermine-poly(dG-dC) binding.
Molecular mechanics calculations of the binding of spermine to a number of solvated DNA helices have led to the development of a new model for spermine complexation. The structural details of the complexes formed with d(GCGCGCGCGC)2 and d(ATATATATAT)2 decamers allowed a rationalization of the observed experimental differences for binding to these two helices. For d(ATATATATAT)2 it was concluded that spermine remains in a cross-major groove binding site. Conversely, for d(GCGCGCGCGC)2 spermine reorientation via specific ligand-base-pair hydrogen-bond formation allows complexation along the major groove. The solvent plays an important role in differentiating the two binding modes. A mechanism of spermine complexation to natural DNA is postulated from these results. Past experimental data are also considered in the context of the new model.
Similarity of molecular shape.
The similarity of one molecule to another has usually been defined in terms of electron densities or electrostatic potentials or fields. Here it is expressed as a function of the molecular shape. Formulations of similarity (S) reduce to very simple forms, thus rendering the computerised calculation straightforward and fast. 'Elements of similarity' are identified, in the same spirit as 'elements of chirality', except that the former are understood to be variable rather than present-or-absent. Methods are presented which bypass the time-consuming mathematical optimisation of the relative orientation of the molecules. Numerical results are presented and examined, with emphasis on the similarity of isomers. At the extreme, enantiomeric pairs are considered, where it is the dissimilarity (D = 1 - S) that is of consequence. We argue that chiral molecules can be graded by dissimilarity, and show that D is the shape-analog of the 'chirality coefficient', with the simple form of the former opening up numerical access to the latter.
Fast drug-receptor mapping by site-directed distances: a novel method of predicting new pharmacological leads.
The searching and characterization of large chemical databases has recently provoked much interest, particularly with respect to the question of whether any of the compounds in the database could serve as new leads to a compound of pharmacological interest. This paper introduces a fast and novel method of determining whether any of a given series of compounds are able, on geometrical grounds, to interact with an active site of interest. The C program written to implement the method is able to make a qualitative prediction for a given compound in about 1 s per structure (for drug-sized molecules), while still permitting the compound complete conformational freedom. However, the algorithm is sufficiently flexible to permit distance constraints to be placed on the molecules while docking. The test system studied was a family of Baker's triazines docking into the active site of dihydrofolate reductase (DHFR), as defined by a methotrexate/NADPH complex.
Molecular modelling of the sterol C-14 demethylase of Saccharomyces cerevisiae.
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Sequence selective binding to the DNA major groove: tris(1,10-phenanthroline) metal complexes binding to poly(dG-dC) and poly(dA-dT).
Molecular modelling and energy minimisation calculations that incorporate solvent effects have been used to investigate the complexation of delta and lambda-[Ru(1,10-phenanthroline]2+ to DNA. The most stable binding geometry for both enantiomers is one in which a phenanthroline chelate is positioned in the major groove. The chelate is partially inserted between neighbouring base pairs, but is not intercalated. For delta, though not for lambda, a geometry with two chelates in the major groove is only slightly less favourable. Minor groove binding is shown to be no more favourable than external electrostatic binding. The optimised geometries of the DNA/[Ru(1,10-phenanthroline]2+ complexes enable published linear dichroism spectra to be used to determine the percentage of each enantiomer in the two most favourable major groove sites. For delta 57 +/- 15% and for lambda 82 +/- 7% of bound molecules are in the partially inserted site.
A binding mode of lambda-[tris(1,10-phenanthroline)ruthenium(II)]2+ exhibiting preference for purine-3',5'-pyrimidine sites of DNA.
Molecular mechanics calculations and molecular dynamics simulations have been used to study the binding of the partially inserted major groove complex of Lambda-[Ru(1,10-phenanthroline)3]2+ with DNA. Energy refinements of this complex showed a clear preference for binding at purine-3',5'-pyrimidine sites over pyrimidine-3',5'-purine sites. The basis for this difference is shown to be a slight change in the binding orientation induced by interchanging the purine and pyrimidine bases. This in turn provides for a better secondary interaction with the helix backbone at a point beyond the immediate binding site. It is this secondary interaction that provides the additional energetic stabilisation for complexes formed at purine-3',5'-pyrimidine sites. Molecular dynamics simulations including explicit representation of solvent support these conclusions and provide an insight into the positional stability of the ligand at a particular site. Repuckering of specific deoxyribose rings to the C3'-endo conformation seems to be an important feature of the DNA/ligand complex.
A prototype bioreductive DNA groove binding ligand.
Molecular mechanics calculations have been used to evaluate the potential bioreductive behaviour of several DNA minor groove binding ligands containing quinone/hydroquinone redox systems. The proposed structures are analogues of the Hoechst 33258 molecule with modifications of the benzimidazole rings. Binding energies of simple analogues indicate the reduced forms bind more strongly to the DNA minor groove. N-methylation of the imidazole ring(s) produces structures which can form extended quinone methides. These also show stronger binding in the reduced form and it is speculated that such structures might provide a basis for the design of groove binding ligands which will act as bioreductive alkylating agents.
Histamine tautomerism and its mode of action.
An established combination of quantum mechanical calculations and molecular dynamics simulations (Worth, C.A., King, P.M. and Richards, W.G. (1989) Biochim. Biophys. Acta 993, 134-136; Cieplak, P., Singh, U.C. and Kollman, P.A. (1987) Int. J. Quant. Chem. QBS14, 65-74; Reynolds, C.A., King, P.M. and Richards, W.G. (1988) Nature 334, 80-82) has been used to calculate the tautomer ratios of histamine species in aqueous solution. The results are in good agreement with experiment and provide a bridge between experimental data and earlier theoretical calculations.
Molecular similarity: the introduction of flexible fitting.
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Associative learning changes intrinsic to Hermissenda type A photoreceptors.
The eyes of the nudibranch mollusc Hermissenda have previously been shown to contain 2 classes of photoreceptors. Type B photoreceptors exhibit increased light responses and membrane excitability after repeated pairings of light and rotation and play an important role in the mediation of associatively produced reductions in phototactic behavior. Type A photoreceptors have also been shown to change with associative training. In previous research, Type A photoreceptors from trained animals were found to have reduced light responses. Because these recordings were obtained from synaptically intact cells, it was not possible to determine whether the effects of associative training reflected changes in synaptic input to Type A photoreceptors or intrinsic changes in somatic conductances. In the present study, intracellular recordings from synaptically isolated Type A photoreceptors were obtained on retention days after training, and pairing-specific decreases in light-induced generator potentials and decreases in resting input resistance were observed. Current- and voltage-clamp analysis of Type A photoreceptors from untrained animals revealed that an important determinant of the steady-state light response was a calcium-activated K+ current (IK-Ca). Thus, Type A photoreceptors also appear to be a primary site for associative information storage in Hermissenda. It is suggested that enhancement of IK-Ca by associative training may contribute to the diminished light response of Type A photoreceptors.
Netropsin binding to poly[d(IC)].poly[IC)] and poly[d(GC].poly[d(GC)]: a computer simulation.
The thermodynamic cycle perturbation approach has been used to calculate the difference in the free energy of binding of netropsin to two different DNA molecules. In the computer simulations, all the inosine residues have been gradually 'mutated' into guanosine in a DNA dodecamer and in a complex of the same dodecamer with netropsin. The difference in binding free energy of about 4.3 kcal mol-1 agrees well with the experimentally determined value of 4.0 kcal mol-1. One structural determinant of the specificity seems to be the width of the minor groove in the two complexes.
Theoretical calculation of tautomer equilibria in solution: 4-(5-)methylimidazole.
A combination of quantum mechanical calculations and molecular dynamics simulations has been used to calculate the tautomer ratio of 4-(5-)methyl imidazole in solution, and the results are in good agreement with experiment.