Frontiers in Computational Chemistry: Volume 4

Zaheer Ul-Haq Qasmi, Angela K. Wilson, Zaheer Ul-Haq Qasmi, Angela K. Wilson

• Publisher: Bentham Science Publishers
• Year: 2018
• Print ISBN:
  9781681084428
• eBook ISBN:
  9781681084411
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

Frontiers in Computational Chemistry presents contemporary research on molecular modeling techniques used in drug discovery and the drug development process: computer aided molecular design, drug discovery and development, lead generation, lead optimization, database management, computer and molecular graphics, and the development of new computational methods or efficient algorithms for the simulation of chemical phenomena including analyses of biological activity. The fourth volume of this series features four chapters covering natural lead compounds, computer aided drug discovery methods in Parkinson's Disease therapy, studies of aminoacyl tRNA synthetase inhibition in bacteria, computational modeling of halogen bonds in biological systems and molecular classification of caffeine and its metabolites.

Molecular Classification of Caffeine, Its Metabolites and Nicotine Metabolite

Francisco Torrens^{1, *}, Gloria Castellano²

¹ Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, P.O. Box 22085, E-46071 València, Spain

² Departamento de Ciencias Experimentales y Matemáticas, Facultad de Veterinaria y Ciencias Experimentales, Universidad Católica de Valencia San Vicente Mártir, Guillem de Castro-94, E-46001 València, Spain

Abstract

Methylxanthines (caffeine and its metabolites) and cotinine were analyzed by liquid chromatography–tandem mass spectrometry in man blood and urine. Retention times are represented by structure–property relationships. Biological plastic evolution is an evolutionary approach combining the result of acquired features and evolutionary indeterminacy–morphological determination–natural selection principles. Its use in planning co-ordination descriptor gives powerful associations. The objective is to develop a structure–property relation for qualitative and quantitative prediction of xanthines retentions. Results contribute to xanthines relation prediction in man blood and urine samples. Code MOPAC-AM1 allows molar formation enthalpy, and TOPO, fractal indices, which show that for a given atom, energies and dimensions are sensitive to the presence in the molecule of functional groups. Formation enthalpy, fractal dimensions, etc. differentiate xanthines. Parameters needed for co-ordination descriptor are formation enthalpy, molecular weight and bare surface area. Categorization procedures are founded on information entropy and making. Xanthines allow a structural classification by the figures of C+N+O and O atoms. Dissimilar performance depend on the figure of C+N+O atoms. The innovation of the method is that two count descriptors result connected to retention time. On using classification algorithms in modest-extent collections, too much outcomes result matching to information, bearing a combinatorial explosion. Notwithstanding, equipartition conjecture chooses a criterion from categorization among hierarchical trees. Information entropy allows categorizing molecules in accord with principal components analyses. Hierarchical cluster and principal components analyses categorize xanthines into three groupings and produce acceptable performance. Categorization benefit results in estimating retention times for substances not comprised in the grouping. Caffeine is a drug model because it is one of the most studied medicines. It is the world’s most widely consumed psychoactive drug. Theobromine serves as lead for drugs development.

Keywords: Molecular classification, Information entropy, Entropy production, Equipartition conjecture, Principal components analysis, Cluster analysis, Metabolite, Clinical analysis, Caffeine, Nicotine, Xanthine, Cotinine.

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^* Corresponding author Francisco Torrens: Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, P.O. Box 22085, E-46071 València, Spain; Tel. [phone]; Fax: [phone]; E-mail: [email protected]

INTRODUCTION

The determination of purine alkaloid methylxanthines [caffeine (Caff), and its metabolites theobromine, paraxanthine and theophylline, cf. Fig. (1e, b, c, d) in man blood and urine is based on liquid chromatography (LC) coupled to ultraviolet (UV) spectrophotometric detection or mass spectrometry (MS). Sensing UV provides low selectivity, since endogenous compounds present in biofluids interfere with the target analytes. The LC coupled to single MS (LC-MS) [1, 2] or tandem MS (LC-MS-MS) [3, 4] were applied for the analysis of oxopurine methylxanthines in man biofluids. The LC-MS-MS provides better sensitivity and selectivity than LC-MS. Published LC-MS and LC-MS-MS methods are based on direct sample injection before LC column-switching, or centrifugation and filtration followed by sample dilution to reduce matrix impact on the chromatographic determination. The most frequently used technique for the determination of alkaloid nicotine metabolite cotinine (Fig. 1a, g), in man fluids, is gas chromatography (GC) coupled to MS (GC-MS). The LC-MS and LC-MS- MS were successfully applied for the analysis of cotinine in biomatrices [5]. Photoionization (PI) MS and valence PI of hypoxanthine (Hyp), xanthine (Xan) and Caff were reported. Degradation of Caff was observed during green (GT)/black-tea (BT) oxidation (fermentation) [6^-8]. Quantitative structure–activity/property relationships (QSARs/QSPRs) of Caffs were informed by similarity cluster prediction. Bossi and Bech built on and confirmed a multi-residue approach for the examination of methylxanthines and cotinine in man blood [9]. Their method involved off-line solid-phase (SP) extraction (SPE) and analysis by LC-MS-MS with electrospray ionization (ESI) in positive ion (PoI) mode. Their developed and validated method resulted fast, selective and convenient for the simultaneous determination of cotinine, Caff and its metabolites in man blood, which was useful to assess man exposure to tobacco smoke and coffee consumption. They successfully applied the method to the analysis of 500 samples from pregnant women in a clinical study.

Some foods, drinks and beverages interact with cytochrome P450 (CYP), e.g., 1A2, activating (e.g., milk) or inhibiting them (e.g., grapefruit juice), so decreasing or increasing, respectively, the half-life of venoms, drugs and xenobiotics in the organism [10]. However, grapefruit juice did not interact with alkaloid theophylline, which was expected since this presents complete oral bioavailability. Theophylline is not a substrate for CYP3A4....

Table of contents

• Welcome
• Table of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• PREFACE
• List of Contributors
• Natural Lead Compounds and Strategies for Optimization
• Computer-aided Drug Discovery Methodologies in the Modeling of Dual Target Ligands as Potential Parkinson’s Disease Therapeutics
• Molecular Studies of the Inhibition of Aminoacyl tRNA Synthetases in Microbial Pathogens
• Advances in the Computational Modeling of Halogen Bonds in Biochemical Systems
• Molecular Classification of Caffeine, Its Metabolites and Nicotine Metabolite