CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Medicinal ChemistryCHM 2004 Fall 2010

Professor Sapan ParikhDepartment of Chemistry Manhattanville College

Contact Information

Office Hours Mondays and Tuesdays 2:30 4 PM & by appointment

Office: Brownson 117 or 3A

Phone: (914) 323 5332 / 5401

Email: parikhs@mville.edu

CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Textbook

Fundamentals of MedicinalChemistry, Gareth Thomas,John Wiley & Sons, New York2003

Organic Chemistry Textbook Biochemistry Textbook

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Course Description and Objective

Students who are successful in this course will gain basic understanding of:

the relationship between the structure of a drug and its pharmacological activity the methods and techniques involved in the design and development of pharmaceutical agents state of the art approaches to the development of therapeutics for various disorders

The properties and reactivity of organic functional groups is the foundation of thiscourse. To perform well in this course, it will be very important for each student to bewell versed in the chemistry of the organic functional groups. Do not attempt tomemorize large volumes of information in this course, but try to understand theconcept of structure-activity relationships.

This course is designed to provide an introduction to the chemistry and techniquesinvolved in the design and development of pharmaceutical agents. The nature ofdrugs has changed dramatically over last 20 years. This was facilitated by theavailability of significant amounts of information through proteomics, genomics,combinatorial synthesis and highly efficient analytical techniques. These advanceshave also made the field of Drug Discovery a dynamic one with approaches, methodsand theories evolving at an alarming rate.

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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Grading

25 % - Discussion Group / Short Papers40 % - Two Midterm exam35 % - Individual Research Presentation (15%) & Paper (20%)

100 % - Total

Discussion Group / Short Papers: During the semester, articles from current literaturewill be distributed from the Journal of Medicinal Chemistry, Bioorganic and MedicinalChemistry Letters or Chemical Biology. One student will be selected to lead thediscussion session (prepare slides and notes); however, everyone is responsible forunderstanding the article and contributing to the discussion. Guidelines, content, andformat of the paper will be given during the semester.

Exams: Two midterm exams will be given on dates listed below. The grade for a missedexamination is zero, and there are no make-up examinations. If you need to miss ascheduled exam date please let me know in advance. The exams will cover the lecturematerial, text material, as well as reading from the primary literature.

Exam 1 Monday October 11th Exam 2 Monday November 22th

Grading

A 90 - 100%B 80 - 89%C 70 - 79%D 60 - 69%

F

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Course Outline

Chapter Topic1 Biological Molecules2 An Introduction to Drugs and their Action3 An Introduction to Drug Discovery4 The SAR and QSAR Approaches to Drug Design5 Computer Aided Drug Design6 Combinatorial Chemistry7 Selected Examples of Drug Action at some Common Target Areas8 Pharmacokinetics9 Drug Metabolism

10 An Introduction to Lead and Analogue Syntheses11 Drug Development and Production

Rethinking Drug Discovery......Science, 2004, 303 pg. 1795Surviving the Blockbuster SyndromeScience, 2004, 303 pg. 1796 1799Organic Chemistry in Drug Discovery...Science, 2004, 303 pg. 1810 1813The Many Roles of Computational in Drug DiscoveryScience, 2004, 303 pg. 1813 1817Drug Delivery System: Entering the MainstreamScience, 2004, 303 pg. 1818 1822

Articles

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Chapter 1Biological Molecules

1.1 - Introduction1.2 - Amino acids (structure and Nomenclature)1.3 - Peptides and proteins (Structure)1.4 - Carbohydrates (Monosaccharides, Glycosides and Polysaccharides)1.5 - Lipids (Fatty acids, Steroids, Terpenes, Phospholipids and Glycolipids)1.6 - Nucleic acids (DNA, RNA and Genes and the Human Genome Project)

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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Biological Molecules 1.1 Introduction

Chemical compounds / metallic ions are the basic building blocks of all biologicalstructures and processes that are the basis of life as we know it.

Naturally occurring compounds and ions (endogenous species) are present only invery small amounts in specific regions of the body, whilst others, such as peptides,proteins, carbohydrates, lipids and nucleic acids, are found in all parts of the body.

Basic fundamental knowledge of the nomenclature and structures of these morecommon endogenous classes of biological molecules is essential to understandingMedicinal Chemistry.

Biologically active molecules usually contain more than one type of functional group.(these molecules are a mixture of those of each of the functional groups present plusproperties characteristic of the compound)

Interaction of adjacent functional groups and/or the influence of a functional group onthe carbonhydrogen skeleton of the compound. This often involves the electronicactivation of CH bonds by adjacent functional groups.

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Biological Molecules 1.2 Amino Acids Simple amino acids are the basic building blocks of proteins (their structures containboth an amino group, usually a primary amine, and a carboxylic acid)

The structures of amino acids can also contain other functional groups besides theamine and carboxylic acid groups (Methionine, for example, contains a sulphidegroup, whilst Serine has a primary alcohol group)

Methionine Serine

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Biological Molecules 1.2 Amino Acids (16) The nature of the side chains of aminoacids determines the hydrophobic (waterhating) and hydrophilic (water loving)nature of the amino acid.

Amino acids with hydrophobic side chainswill be less soluble in water than those withhydrophilic side chains. The hydrophobic/hydrophilic nature of the side chains ofamino acids has a considerable influenceon the conformation adopted by a peptideor protein in aqueous solution.

Hydrophobic/hydrophilic balance of thegroups in a molecule will have aconsiderable effect on the ease of itspassage through membranes

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Biological Molecules 1.2 Amino Acids (20)Acid/Base

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Biological Molecules 1.2.2 Structure

All solid amino acids exist as dipolar ions known as zwitterions.

In aqueous solution the structure of amino acids are dependent on the pH of thesolution.

The pH at which an aqueous solution of an amino acid is electrically neutral isknown as the isoelectric point (pI) of the amino acid.

Isoelectric point values vary with temperature.

They are used in the design of electrophoresis and chromatographic analyticalmethods for amino acids.

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Biological Molecules 1.2.3 Nomenclature

Amino acids are normally known by their trivial names (see Table 1.1).

In peptide and protein structures their structures are indicated by either three lettergroups or single letters. Amino acids such as ornithine and citrulline, which are notfound in naturally occurring peptides and proteins, do not have an allocated three orsingle letter code.

ornithine (urea cycle)citrulline (watermelon, urea cycle) 14

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Biological Molecules 1.2.3 Nomenclature

Most amino acids, with the notable exception of glycine, are optically active. Theirconfigurations are usually indicated by the D/L system rather than the R/S system.

Most naturally occurring amino acids have an L configuration but there are someimportant exceptions. For example, some bacteria also possess D-amino acids. Thisis important in the development of some antibacterial drugs.

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Biological Molecules 1.3 Peptides & Proteins Peptides and proteins have a wide variety of roles in the human body. They consistof amino acid residues linked together by amide functional groups, which inpeptides and proteins are referred to as peptide links. The amide group has a rigidflat structure. The lone pair of its nitrogen atom is able to interact with the p electronsof the carbonyl group.

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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Biological Molecules 1.3 Peptides & Proteins

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The term peptide is normally used for compounds that contain small numbers ofamino acid residues whilst the term polypeptide is loosely used for larger compoundswith relative molecular mass (RMM) values greater than about 500 or more.

Proteins are more complex polypeptides with RMM values usually greater than2000. They are classified as simple when their structures contain only amino acidresidues and conjugated when other residues besides those of amino acids occur asintegral parts of their structures.

Hemoglobin is a conjugated protein because its structure contains a heme residue.These non-amino-acid residues are known as prosthetic groups when they areinvolved in the biological activity of the molecule.

Conjugated proteins are classified according to the chemical nature of their non-amino-acid component. For example, glycoproteins contain a carbohydrate residue,hemeoproteins a heme group and lipoproteins a lipid residue.

Biological Molecules 1.3 Peptides & Proteins

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Biological Molecules 1.3 Peptides & Proteins

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Biological Molecules 1.3.1 Structure The structures of peptides and proteins are very varied. They basically consist ofchains of amino acid residues.

These chains may be branched due to the presence of multi-basic or acidic aminoacid residues in the chain.

In addition, bridges (cross links) may be formed between different sections of thesame chain or different chains. Cysteine residues, for example, are responsible forthe SS bridges between the two peptide chains that form the structure of insulin.

The basic structure of peptides and proteins is twisted into a conformation (timedependent overall shape) characteristic of that peptide or protein. Theseconformations are dependent on both the nature of their biological environment aswell as their chemical structures.

The ability of peptides and proteins to carry out their biological functions isnormally dependent on this conformation.

Any changes to any part of the structure of a peptide or protein will either change ordestroy the compounds biological activity. 20

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Biological Molecules 1.3.1 Structure

Figure 1.7 - Representations of the primary structures of peptides. Two systems of abbreviations are used to represent primary structures. The single letter system is used for computer programs.

(a) Met-enkephalin, this pentapeptide occurs in human brain tissue. (b) Glutathione, an antioxidant, protects cells from toxins such as free radicals.(c) -Endorphin, this endogenous peptide has opiate activity and is believed to be produced in the body to counter pain. (d) Viomycin, is an polypeptide antibiotics used in the treatment of tuberculosis. (e) Insulin, the hormone that is responsible for controlling glucose metabolism

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Biological Molecules 1.3.1 Structure For example, sickle-cell anaemia is caused by the replacement of a glutamine (Q)residue by a valine (V) residue structure of hemoglobin.

Proteins are often referred to as globular and fibrous proteins according to theirconformation.

Globular proteins are usually soluble in water (hydrophilic), while fibrous proteinsare usually insoluble (hydrophobic).

The complex nature of their structures has resulted in the use of a sub classification,sometimes referred to as the order of protein structures. This classification dividesthe structure into primary, secondary, tertiary and quaternary orders of structures.

The primary protein structure of peptides and proteins is the sequence ofamino acid residues in the molecule.

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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010

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Biological Molecules 1.3.1 Structure The primary protein structure of peptides and proteins is the sequence ofamino acid residues in the molecule. (Example MAGVHSP.)

Secondary protein structures are the local regular and random conformationsassumed by sections of the peptide chains found in the structures of peptides andproteins.

The main regular conformations found in the secondary structures of proteins arethe -helix, the -pleated sheet and the triple helix. These and other random conformations are believed to be mainly due tointramolecular hydrogen bonding between different sections of the peptide chain.

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Biological Molecules 1.3.1 Structure(a) Hydrogen bondingbetween peptide links. Theconjugated lone pair of theamide nitrogen atom is notavailable to form hydrogenbonds.

(b) The -helix. The peptidechain is largely held in thisshape by intramolecularHydrogen bonds.

(C) The -Pleated sheets are formed by hydrogen bonding between neighboring peptide chains. Antiparallel -sheets have the peptide chains running in opposite directions.

(d) The triple helix in which the three peptide chains are largely heldtogether by hydrogen bonding. For example, the basis of the structure of thefibrous protein collagen which occurs in skin, teeth and bones, consists ofthree chains of the polypeptide tropocollagen in the form of a triple helix.This forms a cable like structure known as a protofibril.

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