EXERCISE III.2 A LABORATORY COURSE IN MEDICINAL LABORATORY COURSE IN MEDICINAL CHEMISTRY INTRODUCING...

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Transcript of EXERCISE III.2 A LABORATORY COURSE IN MEDICINAL LABORATORY COURSE IN MEDICINAL CHEMISTRY INTRODUCING...

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    EXERCISE III.2

    A LABORATORY COURSE IN MEDICINAL CHEMISTRY INTRODUCINGMOLECULAR MODELING

    Ivone Carvalho*, Mnica T. Pupo, urea D. L. Borges, and Lilian S. C. Bernardes

    Departmento de Cincias Farmacuticas de Ribeiro Preto, Universidade de S. Paulo, Av. do cafs/n 14040-903, Ribeiro Preto, SP, Brazil

    E-mail: carronal@usp.br

    Abstract: A laboratory course in medicinal chemistry introducing molecularmodeling. Molecular modeling is an important and useful tool in drug designand for predicting biological activity in library compounds. A wide variety ofcomputer programs and methods have been developed to visualize the 3Dgeometry and to calculate the physicochemical properties of drugs. In thispaper, we describe a practical approach to molecular modeling as a powerfultool to study structureactivity relationship in drugs such as antibacterials,hormones, and cholinergic and adrenergic agents. Early in the course, thestudents learn how to draw 3D structures and to use them to performconformational and molecular analyses. Thus, they may compare drugs withsimilar pharmacological activities by superimposing their structures andevaluating geometry and physical properties.

    Keywords: molecular modeling; conformational analysis; structureactivityrelationships.

    INTRODUCTION

    Planning and selecting educational activities in the teaching of medicinal chemistry are everconstant and necessary tasks in adapting program contents to meet the challenges of aworld in permanent change. Transformations should direct the course in medicinalchemistry to favor the use of new technological resources and contribute to develop bothalternative ways and the students critical thinking. Some methodological strategies shouldbe incorporated into the teaching of medicinal chemistry, thus promoting the teaching-learning processes.1

    The classical structureactivity relationship (SAR) studies implied the synthesis ofseveral, structurally related analogs to a lead compound and successive biological activitytests. After decades of SAR research, some general rules on the influence of specificstructural changes on biological activity could be drawn, including the size and shape of thecarbon chain, the nature and rate of substitution, and stereochemistry of lead compounds.SAR and the traditional techniques of molecular modifications are still important tools in

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    the search for new drugs, but they are expensive, highly time-consuming, and eventuallysuccessful.2

    Chemical computer programs and the Web databases are important tools in thecurrent search for and design of drugs. A series of interesting molecules can be rapidlyscreened as to their biological activity versus physicochemical properties. New therapeuticagents can be developed, analyzing theoretical data on structureactivity in the 3D form,obtained through recent molecular modeling techniques. In a broad definition of medicinalchemistry, relating the invention, discovery, planning, identification, and preparation ofbiologically active compounds, to the study of its metabolism, mechanism of molecularaction, and construction of SARs, it is highly important to insert and approach topics inmolecular modeling in graduation courses on medicinal chemistry.3

    According to IUPAC, molecular modeling is an investigation of structures andmolecular properties by using techniques of computational chemistry and graphicvisualization aiming to obtain, under certain circumstances, a 3D representation.4Computer-assisted drug design (CADD) is described in many sites on the Internet, helping,through tutorials, the investigation of receptor-ligant chemical interactions and theexploring of structural factors connected to biological effects.5 As a result, the integrationof essential knowledge in organic chemistry, biochemistry, molecular biology, andpharmacology, contributes to the understanding of the mechanisms in drug molecularactions.

    The laboratory course in medicinal chemistry is presented to the fifth-periodPharmacy students (30 h, 2 groups) in parallel to the theoretical course (60 h). After carefulanalysis of the different approaches, laboratory practices were directed to the study of thegeometry and properties of drugs, enabling the students to explore the chemical andmolecular basis of the drugreceptor interaction, by employing computational techniques.

    More specifically, the objectives are:(i) conformational analysis of drugs by visualizing its 3D format.(ii) analysis of the size and shape of the pharmacophore(iii) importance of the nature and rate of functional groups substitution(iv) stereochemical aspects of drugs and their relation to biological activity(v) to relate a single series of drugs trough structures and physical properties(vi) to predict molecular mechanisms involved in drug action

    Methods and computational resources employed in the drawing, accurate structuralrepresentation, and 3D visualization of drugs are initially presented in this paper; this isfollowed by showing the use of molecular modeling in the theoretical determination ofphysicochemical properties and comparison of data obtained with adrenergic andcholinergic drugs, active in the autonomic nervous system.

    This approach significantly contributes both to an integration of theoretical andlaboratory data in structureactivity of drugs, and to the implementation of practicalcourses in medicinal chemistry.

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    EXPERIMENTAL

    Drawing, conformational, and molecular analysis of drugs

    Drawing and 3D visualizationSeveral easily utilized programs are available for building bidimensional molecules likeChemWindow, Isis Draw, and ChemDraw. Accurate and high-quality figures and diagramscan be elaborated with the help of such programs that frequently contribute todocumentation and communication in science.

    The students learn the resources available in the main menu of ChemDraw6 andChem3D7 and how to utilize the tool and template selection to design chemical structures.The stereochemical aspects are discussed in depth and through exercises, they are able tocorrectly represent the asymmetrical carbons of drugs like benzylpenicillin (1) andestramustine (2), Fig. 1. Eventually, the structures can be drawn in perspective,representing the molecules in the projections of Fisher, Newman, and Haworth.

    OO

    HN

    N

    SH H

    COOH ON

    CH3OPO3Na2

    O

    Cl

    Cl

    H

    H

    Benzylpenicillin (1)

    Estramustine phosphate (2)

    C16H18N2O4SMolecular weight.: 334.39

    C, 57.47; H, 5.43; N, 8.38; O, 19.14; S, 9.59

    C23H30Cl2NNa2O6PMolecular weight: 564.35

    C, 48.95; H, 5.36; Cl, 12.56; N, 2.48; Na, 8.15; O, 17.01; P, 5.49

    H

    Fig. 1 Drug drawings showing relevant stereochemical features (ChemDraw).

    Several molecular properties can be calculated and/or represented in some of theprograms as well as the molecular formulae, molecular weights and the theoreticalelementary analysis. More sophisticated programs like ChemDraw Ultra8 can, in addition,predict 1H and 13C chemical shifts in NMR of chemical compounds, their freezing andmelting points, log P, molar refractivity, and heat of formation, besides furnishing thecorrect chemical name (IUPAC).

    The students are trained to chemically recognize heterocyclic rings, frequentlypresent in drugs, through the use of the main menu of ChemDraw by clicking on Edit andInsert name as Structure. By introducing the English ring name in the dialog box, it ispossible to visualize the corresponding chemical structure in the drawing window and theaccepted IUPAC nomenclature, which helps the student build complex molecules.

    In the Chem3D7 program, drugs are three-dimensionally visualized, by the gradualbuilding of bonds based on information on their length and position angles. More complexmolecules can be obtained by alternating several of the available resources such as drawing

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    tools, whole substructures ready in the program and the dialog box, where formulae inlinear representation are typed. In parallel, molecules generated in ChemDraw (copy) canbe converted to the 3D model in Chem3D (paste), as shown in Fig. 2 forsulfamethoxazole (3).

    H2N

    NH

    SN

    OOO

    CH3

    (3)

    Fig. 2 Conversion of the 3D sulfamethoxazole (3) structure into the cylindrical bond 3D display (ChemDraw-Chem3D).

    In the Chem3D program, the molecule can be drawn in different formats, such asbackbone, ball and stick, and space filling by using standard length and bond angle values,Fig. 3.

    (3a) (3b) (3d)(3c)

    Fig. 3 Different representations of sulfamethoxazole: (3a) wire, (3b) cylinder and sphere, (3c) cylinder, and(3d) space filling (Chem3D).

    Handling 3D molecular models from Chem3D7 or Molecular Modeling Pro9programs can assess relevant stereofeatures of drugs, allowing information about the size,volume, and shape of the molecules.

    The importance of the stereochemistry in the mechanism of action of drugs isillustrated by epinephrine (4) and propranolol (5), acting on -adrenergic receptors, Fig. 4.Compounds 4 and 5 can be easily drawn in their active configurations, R and S,respectively, by rotating the molecules around the X, Y, Z axis and attributing according tothe classical rule of CahnIngoldPrelog. The configurations of the asymmetrical carbonin the side chains are apparently opposite, due to R and S nomenclature, but in comparison,the 3D representations show that the disposition and spatial orientation of the hydroxylgroups are similar, both directed to the same face. The difference in their naming, R and S,is due to the priority rule, the aryloxy group in the antagonist (5) has priority over themethylenamino group of th