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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: [email protected]
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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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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010
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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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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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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.
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CHM 2004 - Medicinal Chemistry CHM 2004 - Fall 2010
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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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