CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Medicinal Chemistry
CHM 2004 Fall 2010

Professor Sapan Parikh

Department 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

Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Textbook

Fundamentals of Medicinal
Chemistry, Gareth Thomas,
John Wiley & Sons, New York
2003

Organic Chemistry Textbook

Biochemistry Textbook

Course Description and Objective

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

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 this
course. To perform well in this course, it will be very important for each student to be
well versed in the chemistry of the organic functional groups. Do not attempt to
memorize large volumes of information in this course, but try to understand the
concept of structure-activity relationships.
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Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Grading
25 % - Discussion Group / Short Papers
40 % - Two Midterm exam
35 % - Individual Research Presentation (15%) & Paper (20%)
100 % - Total

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

Discussion Group / Short Papers: During the semester, articles from current literature
will be distributed from the Journal of Medicinal Chemistry, Bioorganic and Medicinal
Chemistry Letters or Chemical Biology. One student will be selected to lead the
discussion session (prepare slides and notes); however, everyone is responsible for
understanding the article and contributing to the discussion. Guidelines, content, and
format of the paper will be given during the semester.
Exams: Two midterm exams will be given on dates listed below. The grade for a missed
examination is zero, and there are no make-up examinations. If you need to miss a
scheduled exam date please let me know in advance. The exams will cover the lecture
material, text material, as well as reading from the primary literature.
Exam 1 Monday October 11th

Exam 2 Monday November 22th

Grading
Individual Research Project:
Individual project research will start early in the course to allow students time to
obtain and read original literature, and allow the instructor to guide students in
developing their research projects. Students will select a topic for individual
literature research leading to a 20 minute presentation and 10-page paper.
The content will include:
(1) a graphical structure
(2) discovery/company
(3) brief review of the synthesis or preparation
(4) compound class and biological effects
(5) mode of action (how does it work)
(6) significance
(7) references

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

Guidelines, content, and format of the paper will be given during the semester.
Individual Research Presentation December 2nd, 6th and 9th, 2010
Individual Research Paper December 9th, 2010

Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Course Outline
Chapter
1

Topic
Biological Molecules

An Introduction to Drugs and their Action

An Introduction to Drug Discovery

The SAR and QSAR Approaches to Drug Design

Computer Aided Drug Design

Combinatorial Chemistry

Selected Examples of Drug Action at some Common Target Areas

Pharmacokinetics

Drug Metabolism

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An Introduction to Lead and Analogue Syntheses

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Drug Development and Production

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

Chapter 1
Biological Molecules
1.1 - Introduction
1.2 - 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)

Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Biological Molecules 1.1 Introduction

Chemical compounds / metallic ions are the basic building blocks of all biological
structures and processes that are the basis of life as we know it.
Naturally occurring compounds and ions (endogenous species) are present only in
very 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 more
common endogenous classes of biological molecules is essential to understanding
Medicinal 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 plus
properties characteristic of the compound)
Interaction of adjacent functional groups and/or the influence of a functional group on
the carbonhydrogen skeleton of the compound. This often involves the electronic
activation 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 contain
both an amino group, usually a primary amine, and a carboxylic acid)

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

Serine

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Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Biological Molecules 1.2 Amino Acids (16)

The nature of the side chains of amino
acids determines the hydrophobic (water
hating) and hydrophilic (water loving)
nature of the amino acid.
Amino acids with hydrophobic side chains
will be less soluble in water than those with
hydrophilic side chains. The hydrophobic/
hydrophilic nature of the side chains of
amino acids has a considerable influence
on the conformation adopted by a peptide
or protein in aqueous solution.
Hydrophobic/hydrophilic balance of the
groups in a molecule will have a
considerable effect on the ease of its
passage through membranes
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Biological Molecules 1.2 Amino Acids (20)

Acid/Base

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Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

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 the
solution.
The pH at which an aqueous solution of an amino acid is electrically neutral is
known 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 analytical
methods 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 letter
groups or single letters. Amino acids such as ornithine and citrulline, which are not
found in naturally occurring peptides and proteins, do not have an allocated three or
single letter code.

citrulline (watermelon, urea cycle)

Professor Parikh

ornithine (urea cycle)

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CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Biological Molecules 1.2.3 Nomenclature

Most amino acids, with the notable exception of glycine, are optically active. Their
configurations 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 some
important exceptions. For example, some bacteria also possess D-amino acids. This
is 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 consist
of amino acid residues linked together by amide functional groups, which in
peptides and proteins are referred to as peptide links. The amide group has a rigid
flat structure. The lone pair of its nitrogen atom is able to interact with the p electrons
of the carbonyl group.

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Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Biological Molecules 1.3 Peptides & Proteins

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Biological Molecules 1.3 Peptides & Proteins

The term peptide is normally used for compounds that contain small numbers of
amino acid residues whilst the term polypeptide is loosely used for larger compounds
with relative molecular mass (RMM) values greater than about 500 or more.
Proteins are more complex polypeptides with RMM values usually greater than
2000. They are classified as simple when their structures contain only amino acid
residues and conjugated when other residues besides those of amino acids occur as
integral 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 are
involved in the biological activity of the molecule.
Conjugated proteins are classified according to the chemical nature of their nonamino-acid component. For example, glycoproteins contain a carbohydrate residue,
hemeoproteins a heme group and lipoproteins a lipid residue.

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Professor Parikh

CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

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 of
chains of amino acid residues.
These chains may be branched due to the presence of multi-basic or acidic amino
acid residues in the chain.
In addition, bridges (cross links) may be formed between different sections of the
same chain or different chains. Cysteine residues, for example, are responsible for
the 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 (time
dependent overall shape) characteristic of that peptide or protein. These
conformations are dependent on both the nature of their biological environment as
well as their chemical structures.
The ability of peptides and proteins to carry out their biological functions is
normally dependent on this conformation.
Any changes to any part of the structure of a peptide or protein will either change or
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destroy the compounds biological activity.

Professor Parikh

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CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

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)
(b)
(c)
(d)
(e)

Met-enkephalin, this pentapeptide occurs in human brain tissue.

Glutathione, an antioxidant, protects cells from toxins such as free radicals.
-Endorphin, this endogenous peptide has opiate activity and is believed to be produced in the body to counter pain.
Viomycin, is an polypeptide antibiotics used in the treatment of tuberculosis.
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 their
conformation.
Globular proteins are usually soluble in water (hydrophilic), while fibrous proteins
are 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 divides
the structure into primary, secondary, tertiary and quaternary orders of structures.
The primary protein structure of peptides and proteins is the sequence of
amino acid residues in the molecule.

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Professor Parikh

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CHM 2004 - Medicinal Chemistry

CHM 2004 - Fall 2010

Biological Molecules 1.3.1 Structure

The primary protein structure of peptides and proteins is the sequence of
amino acid residues in the molecule. (Example MAGVHSP.)
Secondary protein structures are the local regular and random conformations
assumed by sections of the peptide chains found in the structures of peptides and
proteins.
The main regular conformations found in the secondary structures of proteins are
the -helix, the -pleated sheet and the triple helix.
These and other random conformations are believed to be mainly due to
intramolecular hydrogen bonding between different sections of the peptide chain.

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Biological Molecules 1.3.1 Structure

(a)
Hydrogen
bonding
between peptide links. The
conjugated lone pair of the
amide nitrogen atom is not
available to form hydrogen
bonds.

(C) The -Pleated sheets are

formed by hydrogen bonding
between neighboring peptide
chains. Antiparallel -sheets
have the peptide chains running
in opposite directions.

(b) The -helix. The peptide

chain is largely held in this
shape by intramolecular
Hydrogen bonds.

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

Professor Parikh

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