P2Y1 receptor antagonists as novel antithrombotic agents.

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.

Prediction of drug-like molecular properties: modeling cytochrome p450 interactions.

Preventing drug-drug interactions and reducing drug-related mortalities dictate cleaner and costlier medicines. The cost to bring a new drug to market has increased dramatically over the last 10 years, with post-discovery activities (preclinical and clinical) costs representing the majority of the spend. With the ever-increasing scrutiny that new drug candidates undergo in the post-discovery assessment phases, there is increasing pressure on discovery to deliver higher-quality drug candidates. Given that compound attrition in the early clinical stages can often be attributed to metabolic liabilities, it has been of great interest lately to implement predictive measures of metabolic stability/ liability in the drug design stage of discovery. The solution to this issue is wrapped in understanding the basic of the cytochrome P450 (CYP) enzymes functions and structures. Recently, experimental information on the structure of a variety of cytochrome P450 enzymes, major contributors to phase I metabolism, has become readily available. This, coupled with the availability of experimental information on substrate specificities, has lead to the development of numerous computational models (macromolecular, pharmacophore, and structure-activity) for the rationalization and prediction of CYP liabilities. A comprehensive review of these models is presented in this chapter.

Comparison of commercially available genetic algorithms: gas as variable selection tool.

Many commercially available software programs claim similar efficiency and accuracy as variable selection tools. Genetic algorithms are commonly used variable selection methods where most relevant variables can be differentiated from 'less important' variables using evolutionary computing techniques. However, different vendors offer several algorithms, and the puzzling question is: which one is the appropriate method of choice? In this study, several genetic algorithm tools (e.g. GFA from Cerius2, QuaSAR-Evolution from MOE and Partek's genetic algorithm) were compared. Stepwise multiple linear regression models were generated using the most relevant variables identified by the above genetic algorithms. This procedure led to the successful generation of Quantitative Structure activity Relationship (QSAR) models for (a) proprietary datasets and (b) the Selwood dataset.

Ligand distortion modes leading to increased chirality content of Katsuki-Jacobsen catalysts.

The "chirality content" of Katsuki-Jacobsen epoxidation catalysts are computed with the Avnir continuous chirality measure (CCM). An assessment of Mn(salen) molecules from the Cambridge Structural Database shows there exist some variation in CCM and the chirality content for several triplet state complexes of these catalysts purported in the literature to be the active species show even larger CCM values. Several deformation modes were analyzed to examine how chirality content changes as catalyst distortion is induced. The deformations studied include in-plane deformations, cup-shaped puckering, ligand twisting motions, and step-like deformations. Some distortions lead to increases of chirality while others lead to a decrease in chirality content. The most influential distortion modes that can be used for ligand design are twisting and step induction.

Prediction of HPLC conditions using QSPR techniques: an effective tool to improve combinatorial library design.

The purification and characterization of compounds resulting from parallel synthesis or combinatorial chemistry has not yet been optimized to operate as a completely automated high-throughput process. Liquid chromatography/mass spectroscopy (LC/MS) is most commonly employed to carry out the characterization and identification of combinatorial compounds. This desired level of automation can only be accomplished if the separation conditions for every compound in the combinatorial array are known prior to the analysis. This study presents a quantitative structure retention relationship (QSRR) approach to predict the retention time of structurally diverse solutes under 75 different LC/MS conditions. Sixty-two compounds were analyzed using 15 commonly used HPLC columns under 5 different gradient conditions. The solute retention time was used as the dependent variable, and more than 1000 molecular descriptors were calculated for this compound set to generate QSRR models. After the elimination of highly correlated variables and those with zero variance, two different genetic algorithms were applied to identify the most significant descriptors. Following the variable selection, the identified descriptors were used to create QSRR models for each separation condition. The calculated stepwise multiple linear regression models have been proven to be statistically significant and highly predictive, with an average coefficient of determination (R2) of 0.86, an average cross-validated r2 of 0.62, r2 = 0.76, and an average F value of 27.29. The QSRR models can be used to design "analysis-friendly" library purification plates, in which compounds are arranged on the basis of their predicted separation condition and can also be used during the library design phase to flag compounds not amenable to the separation methods in use.

Quantitative chirality analysis of molecular subunits of bis(oxazoline)copper(II) complexes in relation to their enantioselective catalytic activity.

The analysis of the quantitative chirality of molecular subunits of spirocyclic bisoxazoline copper complexes was carried out in order to identify the molecular portions most responsible for the chirality of the whole molecule, and therefore also for its catalytic enantioselectivity. It is shown that the smallest fragment that carries the information on molecular chirality contains only a portion of the bidentate bisoxazoline ligands and most atoms of the two monodentate ligands. The structural parameters that are best correlated to the chirality measures of the studied systems are the bond angles at the bridgehead spiro-carbon atom. A prediction is made for an analogous catalyst with potentially high enatioselectivity.

Elucidation of the chiral recognition mechanism of cinchona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino acids.

A cinchona alkaloid having extraordinary chiral discriminatory powers (alpha = 32.6 for dinitrobenzoyl leucine) is developed as a chiral stationary phase (CSP) for chromatography. An explanation of how chiral discrimination takes place is presented. Using a soluble analogue of the CSP, we found that NMR spectrometry indicates that 1:1 complexes exist for both optical isomers interacting with the CSP, that the free base form of the CSP exists in an open/closed ratio of 35/65 but that the protonated, bound-state form is exclusively in the anti-open conformation, and that significant intermolecular NOEs exist for the more stable diastereomeric complex but not for the less stable complex. Stochastic molecular dynamics simulations were carried out in solvents of low and high dielectric. The chromatographic retention orders and free energy differences of analyte binding to CSP were reproduced computationally as were the observed intra- and intermolecular NOEs. Data from the simulation were used to evaluate the intermolecular forces responsible for analyte binding as well as to discern fragments of the CSP doing most of the work of holding the complexes together. The enantiodifferentiating forces and the parts of the CSP most responsible for chiral discrimination are described. Moments of distributions of key dihedral angles and distances between centroids were used to assess the relative rigidity of the competing diastereomeric complexes. Simultaneous multiple-contact ion-pairing, hydrogen bonding, and pi-stacking are possible for the longer retained enantiomer only. An X-ray crystallographic study of the more stable complex confirms the conclusions derived from chromatography, NMR spectroscopy, and molecular modeling.