Margaret G. Wong

Estimation of pKa Using Semiempirical Molecular Orbital Methods. Part 1: Application to Phenols and Carboxylic Acids.

The electronic properties of small molecules can be calculated quickly and with a reasonable degree of accuracy using semiempirical QM methods. In this study a set of QM properties derived from frontier electron theory have been used to produce a predictive model of the dissociation constants of phenols, benzoic acids and aliphatic carboxylic acids. The pK a values and structures of nearly 500 compounds were extracted from the Physprop database for this purpose. Multiple linear regression was used to search for relationships between pK a and the calculated QM properties. In most cases only a single independent variable, electrophilic superdelocalisability, was needed to produce a good model of pK a . The advantages of our approach are in the speed of calculation and the simplicity of the resultant models. The merits of using semiempirical methods to predict pK a are discussed in relation to previous studies.

Estimation of pKa using semiempirical molecular orbital methods. Part 2: Application to amines, anilines and various nitrogen containing heterocyclic compounds

The pK a of a compound directly influences its biopharmaceutical profile. This article describes the development of a method for estimating pK a values for a number of nitrogen containing chemical structures using semiempirical QM properties derived from frontier electron theory. Typically, the property giving the best correlation with pK d was the electrophilic superdelocalisability of the nitrogen atom resulting in regression equations with r 2 values up to 0.94. The advantages of this technique are in the simplicity of the models and the speed of calculation, suggesting that this method could be widely applied to the estimation of pK a values. The success of this approach is discussed in relation to other methods.

Molecular and pharmacological characterization of the human CCKB receptor

The human cholecystokinin B (CCKB) receptor has been isolated from a human temporal cortex cDNA library. Transient transfection of the receptor into COS-M6 cells resulted in high specific binding of 125I-sulphated CCK-8 labelled with Bolton and Hunter Reagent (KD = 31 pM). Competition experiments yielded the expected CCKB receptor ligand binding profile for agonists and antagonists. Similar results were obtained in human small cell lung carcinoma cells, which express an endogenous CCKB receptor. Extensive functional characterization of the receptor was performed in stably transfected HeLa cells using intracellular calcium imaging and microphysiometry techniques. Molecular analysis of the human CCKB receptor using Southern blotting of genomic DNA suggests the presence of a single gene for the CCKB receptor with no closely related homologues. This was confirmed by the polymerase chain reaction cloning of identical receptor coding sequences from human small cell lung carcinoma cells and human gastric enterochromaffin-like cell-oma (ECLoma) tissue.

Syntheses, pharmacological evaluation and molecular modelling of substituted 6-alkoxyimidazo[1,2-b]pyridazines as new ligands for the benzodiazepine receptor

Summary A series of 2,3-disubstituted-6-alkoxyimidazo[1,2-b]pyridazines has been synthesized and evaluated for in vitro affinity for the benzodiazepine receptor (BZR). 3-(Benzamidomethyl or substituted benzamidomethyl)-6-methoxy-2-(3,4-methylenedioxyphenyl)imidazo[1,2-b]pyridazines were found to be the most potent BZR ligands (eg, 4a, IC50 7 nM; 4e, IC50 14 nM; 4v, IC50 8 nM). Imidazo[1,2-b]pyridazines unsubstituted in the 3-position, or containing bulkier alkoxy groups in the 6-position, were found to bind less strongly to the BZR. Selected compounds from the series were identified from in vitro GABA-shift experiments as BZR agonists. Molecular modelling has been employed to identify the common pharmacophoric points of lipophilic and hydrogen bonding, ligand-receptor interaction and areas of steric hindrance for these substituted imidazo[1,2-b]pyridazines at the BZR.

Objective testing for the dependence of electrophoretic mobilities upon size in capillary zone electrophoresis

SummaryEighteen peptides have been modeled. From the volumetric data derived, and published mobilities, the relationship between electrophoretic mobility (μep) and the hydrodynamic radius(r) has been examined. Objective testing with respect to size has been achieved by the log-log version of generalized relationship. (1) From the gradient of the plot versus log r(2.02) there is good support for the inverse square law (μep α 1/r2). Equivalent calculations using molecular weight (Mr) and the number of amino acid residues (n) similarly lead to μep α 1/Mr2/3 and μep α 1/n2/3, respectively. However, the strength of the correlation is diminished as the precision of the representation of size is degraded. (2) An examination of the effect of size at fixed charge and a statistical analysis of the charge distribution on the peptides leads to the conclusion that deviations from the averaged behaviour arise from a charge-induced volumetric effect. Taken together, (1) and (2) indicate that whilst net charge and total size can describe average electrophoretic behaviour well, these parameters are inadequate to describe the specific mobilities of individual analytes.Objective analysis of alkylpyridine data indicates μep α 1/rx where x=2.6–2.8 (depending upon the nature of the r values utilized), but is certainly ≠1 as may have been presumed. A very small range of values may be responsible for this surprising result.

Molecular field analysis of clozapine analogs in the development of a pharmacophore model of antipsychotic drug action.

In an attempt to elucidate some aspects of clozapines favorable receptor binding profile, we modeled a series of 30 clozapine analogs using a pharmacophore based on the ligands octoclothepin and tefludazine. Molecular field analysis using CoMFA combined with HINT was carried out on published D2 receptor binding affinities. Several alternative alignments of the analogs gave r2 values in the range of 0.8-0.95. The final model had good predictive abilities with q2 > 0.6 and r2 > 0.9. This provides an excellent framework to aid in the design of novel antipsychotics with diminished propensity to produce clinically limiting side effects.

Heterocyclic amino alcohols related to ifenprodil as σ receptor ligands: binding and conformational analyses

The interaction of a novel series of heterocyclic amino alcohols with the sigma receptor site was assessed using radioligand binding and computerized molecular modelling. All heterocyclic amino alcohols, like the structurally related ifenprodil, fully inhibited the specific binding of [3H]R(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [3H]3-PPP and the proportion of sites in the high affinity state was 60-80% of the total sites. Some of the heterocyclic amino alcohols also displayed similar affinity for alpha 1-adrenoceptors labelled by [3H]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [3H]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N-methyl-D-aspartate channel ligand, [3H]-(N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a sigma receptor site model; low energy conformers could be superimposed like other potent sigma receptor ligands with confidence to the sigma receptor model. Our results define a new class of sigma receptor ligands and extend the understanding of the molecular requirements for drugs active at the sigma receptor.

Conformational requirements for convulsant compounds

Abstract The conformations of a structurally diverse series of convulsant drugs sharing a common binding site with picrotoxinin were studied to give some clues as to the mechanisms of epilepsy and thus to the design of anti-convulsant drugs. Both classical potential energy calculations and molecular orbital calculations were used to determine low energy conformations able to bind at the receptor. In addition, electrostatic potential energy surfaces were calculated to establish the most likely sites of electrostatic interaction. This information was then used to determine a common pharmacophore for these compounds.

Molecular Mapping in the CNS

Since ancient times the operation of the brain has elicited more than usual interest. Data mining of the human genome is revealing that many CNS abnormalities have a genetic component. As yet this information can not be used directly to cure or ameliorate specific CNS disorders although this is regarded as having great potential for future therapies. Current CNS drug design and 3D QSAR is based on knowing either the structures of key proteins and how smaller molecules interact with them to obtain a pharmacological response, or on hypothesising about key structural features and interactions by a variety of molecular modelling and computational techniques. Methods used include conformational analyses, pharmacophore development and QSAR which are now being actively applied to increase our understanding of how molecules interact with specific sites within the CNS as a basis for the design of new pharmacologically active compounds. In this review we give an overview of the latest strategies used in 3D-QSAR based drug design and survey the most recent applications of these strategies to the CNS. By way of example, accounts are given of computer-based research aimed at drugs targeting GABA, glutamate, dopamine and opioid receptors.

The hybridization state of nitrogen as a conformational variable in biologically active molecules

A survey of the conformations found in the crystal structures of central nervous system-active drugs and related nitrogen-containing structures shows that there is a continuous distribution of conformations from that typical of the sp3(N-torsion 120°) to that typical of the sp2(N-torsion 180°) hybridization state. In general the presence of an adjacent carbonyl group favours a planar geometry, while the lack of any conjugating group favours the tetrahedral state, but nitrogens with aromatic substituents cover the entire range between the two states. Other than those cases where the nitrogen has aromatic substituents or is in a sterically constrained ring-system (e.g., cage compounds), steric effects have relatively little influence on the conformation at nitrogen. In these cases calculations using various techniques suggest that simple non-bonded potential calculations may be the most practical approach to the evaluation of nitrogen geometry. Even in small molecules, however, calculated barriers to nitrogen inversion are generally low and poorly reproduced by either molecular orbital or classical calculations.