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Medicinal Chemistry: The Molecular Basis of Drug Discovery

Davidson D001x - Medicinal Chemistry - The Molecular Basis of Drug Discovery
Instructor - Erland Stevens - Davidson College
Start of Course - Tuesday, 02 January 2018 at 15:00 UTC
End of Registration - Tuesday, 17 April 2018 at 15:00 UTC
Verified Upgrade Deadline - Tuesday, 01 May 2018 at 15:00 UTC
Grading Deadline - Tuesday, 01 May 2018 at 15:00 UTC
End of Course - Tuesday, 01 May 2018 at 15:00 UTC

I. Learning Objectives

The overall goal of this course is to teach a student how to relate the chemical structure of a drug to its
biological function. An outcome of this goal is that a student who completes this course will be able to attend
lectures on drug discovery and reasonably understand the content of the lectures.

 Recall the major steps of drug development and their corresponding processes
 Interpret relationships between molecule concentration and enzyme or receptor activity
 Compute a molecule's pharmacokinetic parameters from Cp-time data points
 Correlate a molecule's structure to its metabolic behavior
 Prioritize the viability of weakly active molecules for potential drug development
 Propose molecules with improved properties based upon data from related structures

II. Prerequisites

Students should be able to be able to identify organic chemistry functional groups and read line-angle chemical
structures. In the area of general chemistry, students should be familiar with the concepts of equilibrium, free
energy changes, and pKa. Students should also know the parts of a cell and be comfortable working with
mathematical expressions containing exponents and logarithms. Students who lack the necessary organic
chemistry experience may be able to supplement their knowledge through lectures offered by Khan Academy.

III. Required Materials

This course does not have a required textbook. All materials for the course will be provided through the edX
platform. Students have access to a spreadsheet application. Examples include Microsoft Excel, Apache
OpenOffice and LibreOffice (free, downloadable office suite programs), and Google Docs Spreadsheet
(available to anyone with a free Google account). The spreadsheet application will allow analysis of data that
will be encountered throughout the course. The MOOC includes instructions on how to complete tasks with
Google Docs Spreadsheet. The instructions should also be helpful for the use of other spreadsheet applications.

Past students in the course have recommended Web 2.0 calc as a convenient online calculator. Many students
in MOOCs download the video content of the course. A free video player that is highly recommended by
previous students is VLC.

IV. Registration

Students can register for the course under two different categories: audit and verified. Audit students take the
course for free. The verified track costs $49 and requires students to confirm their identity as they log into the
course. Students who intend to use this course as a professional credential may want to consider registering in
the verified category. Students may sample the entire course before switching to verified status. The deadline
for registering for the verified track is the same as the closing date of the course: Tuesday, 01 May 2018 at
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15:00 UTC. (Periodic emails from edX may encourage students to upgrade to verified status at an earlier date,
but the deadline for all students in 01 May 2018.) Students who do plan to register under the verified track are
encouraged to not wait until the late minute as some international payments are slow to process.

Students who are registered under the verified track will receive a certificate of completion if they pass the
course with an overall grade of at least 70%. Students registered in the verified track should receive their
certificates soon. The certificates will be accessible through each student's dashboard. (The original syllabus
stated that certificates are not available until after the course closes. This statement is incorrect.)

V. Course Schedule - course launch Tuesday, 02 January 2018 at 15:00 UTC

All course content will be immediately released and available for viewing and completion. All course
assignments will remain open for grading until the final deadline of the course (Tuesday, 01 May 2018 at 15:00
UTC). The course is broken up into seven, approximately equally-sized modules. While the course is entirely
self-paced, students are advised to work through a module at a pace of around one module per week.

Module 1
Chapter 1 – Pre-Regulatory Medicine
Chapter 2 – Drug Discovery: From Concept to Marketplace
Expert Interview – Natalie Clayton, Partner, Alston & Bird
Virtual Lab – Designing molecules with potency

Module 2
Chapter 3 – Proteins
Chapter 4 – Enzymes
Chapter 5 – Receptors
Expert Interview – Dr. Steven Tregay, CEO, FORMA Therapeutics
Virtual Lab – Designing molecules with potency and selectivity
*** Examination 1 ***

Module 3
Chapter 6 – Blood and Drug Transport
Chapter 7 – Pharmacokinetics
Expert Interview – Dr. Parisa Zamiri, Director, Translational Medicine Expert at Novartis
Virtual Lab – Designing molecules with potency, selectivity, and bioavailability

Module 4
Chapter 7 – Pharmacokinetics (con't)
Chapter 8 – Metabolism
Expert Interview – Dr. James Mangold, Director of DMPK at Novartis
Virtual Lab – Designing molecules with potency, selectivity, bioavailability, and no drug interactions
*** Examination 2 ***

Module 5
Chapter 9 – Structure and Diversity
Expert Interview – Dr. Adam Hill, Head of Screening at Novartis
Virtual Lab – Designing Ibuprofen Analogues with SeeSAR

Module 6
Chapter 10 – Lead Discovery
Expert Interview – Dr. Meir Glick, Head of in silico Lead Discovery at Novartis
Virtual Lab – Designing Histamine Ligands that Do Not Cross the BBB with SeeSAR
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Module 7
Chapter 11 – Lead Optimization
Expert Interview – Dr. Julien Levell, Group Leader in Global Drug Discovery at Novartis
Expert Interview – Dr. Amin Kamel, Senior Research Investigator II at Novartis
Expert Interview – Dr. Parisa Zamiri, Director, Translational Medicine Expert at Novartis
Virtual Lab – Designing an Orally-Available Protease Inhibitor with SeeSAR
*** Examination 3 ***

Final deadline for all graded content - Monday, 01 May 2018 at 15:00 UTC

VI. Grading

The course grade is based on four types of assignments: in-chapter exercises (ICE), examinations (EX), class
participation (CP), chats (CH), and extra credit (EC). The passing grade for this course is 70%. Grades on
individual assignments can be below 70%, but the student's overall grade must be at least 70%.

 in-chapter exercises (ICE) - These assignments are found in almost each subsection of the course. In
general, almost every lecture video will have at least one ICE associated with it. Students may work
with others on the ICEs, and questions to the discussion board on the ICEs is permitted and even
encouraged. The ICEs account for 60% of the total course grade. There are 44 ICEs spread throughout
the 7 modules of the course.
 examinations (EX) - The three exams are found at the end of Modules 2, 4, and 7. Students must work
independently on the exams, although they are free to use all the resources provided in the course to
answer the questions (i.e., open-book and open-note exam). The exams account for 30% of the total
course grade.
 class participation (CP) - Students receive class participation credit by working on the Virtual Labs and
watching the expert interviews. The class participation score counts for 10% of the total course
grade. Each module concludes with both a Virtual Lab and interview.
 extra credit (EC) - Extra credit is available to students for completing surveys at the start and finish of
the course as well as completing the pre- and post-test. Students may add up to 5% of the total possible
points through extra credit (i.e., maximum course grade = 105%).

A comment on the grading of questions

All grade scores assigned within the course are final once a student submits an answer. Given the online
format of the course and the fact that enrollment will include thousands of students, individual grade
adjustments are not feasible. The staff of D001x acknowledges the possibility that some questions in the course
may not be ideally worded or the correct answer may be somewhat subjective. The inclusion of extra credit
points is intended to offset any instances of poorly worded questions.

VII. Honor Code

In order to participate in this or any other edX course, a student must agree to abide by the edX Honor Code
Pledge (scroll down within the linked page). Under the terms of the pledge, students may collaborate on the
questions and exercises in each chapter. The examinations, however, must be completed independently by each
student.

VIII. Discussion Board

The course has a discussion board for interaction between students, course teaching assistants, the instructor,
and technical support staff. Students are encouraged to participate on the discussion board for assistance with
course material and to converse with other students on related topics. Students may discuss course content,
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but any posts that disclose answers to an assessment question will be edited or deleted by the course
staff. Students are expected to follow the guidelines below, which are taken from the World Wide Web
Consortium (W3C) web site. The edX Terms of Service provide similar guidelines for behavior of all edX
participants.

 Tone of messages must be maintained at the highest level of professionalism; flaming, sarcasm, or
personal attacks will not be tolerated.
 Don't attack a person. Disagree with an idea.
 Respect the right of others to disagree.
 Be polite and show respect. If you have nothing new, positive, informative or helpful to say, refrain
from sharing it.
 It's inappropriate to repeat the same argument over and over without adding new information.
 Debate; Don't argue.
 Listen; Don't shout.
 Stay on topic.

Students who fail to adhere to these guidelines will experience one of more of the following consequences.

 Private warning
 Public warning
 Voluntary time out
 Involuntary time out
 Permanent removal from the discussion board

IX. Hints and Tips

 Print the materials for the course

Each video clip has an available summary. Print and read the video summaries for additional insight
into the course material.
 Take notes on both the video and written content of the course
Record your own notes on the printed materials so that you can make connections between the topics.
 Use the discussion board
There is no reason to be confused or frustrated. Reach out to your fellow students and the course staff
through the discussion board. The board is actively monitored throughout the day.
 Protect your time
When working on the course, minimize your distractions, and be prepared to focus on the material. The
more time you put into the course, the more you will receive from it.

Glossary

absorption - the movement of a drug from its site of administration to the bloodstream

active pharmaceutical ingredient (API) - the chemical in an administered drug that is responsible for its
biological activity

adverse effect - an undesired effect of a drug

alkaloid - a molecule found in a natural source with a basic nitrogen and a level of structural complexity
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allosteric site - a site on an enzyme or receptor that is not bound by a substrate or response-causing
ligand. Noncompetitive inhibitors (enzymes) and noncompetitive antagonists (receptors) bind at allosteric sites.

alpha-helix (α-helix) - a type of secondary structure in which the protein backbone assumes a spiral
conformation

amide linkage - the amide bond formed between individual amino acid residues in a protein backbone

analgesic - pain killer

analogues - compounds related to a lead and prepared in an attempt to optimize the desired properties of the
lead

API - see active pharmaceutical ingredient

apparent volume of distribution (Vd) - a hypothetical volume of plasma that is required to contain a specified
drug dose

area under curve (AUC) - the area beneath a Cp-time curve. AUC is a measure of drug exposure.

arsenicals - an early synthetic drug class that was used to treat syphillis and certainly protozoan infections

assay - a general term for testing the biological activity of a molecule. An assay may be performed either in
vivo or in vitro.

AUC- see area under curve

beta-sheet (β-sheet) - a type of secondary structure in which the protein backbone assumes a fairly flat shape
formed by a back-and-forth flow of the chain

binding energy - the free energy of binding between a drug and its target based on the dissociation equilibrium
constant between the drug and target (K)

bioavailability (F) - the fraction of an drug dose that actually reaches the bloodstream from its site of
administration

bioequivalence testing - an abbreviated clinical trial used by generic manufacturers to show that a generic
product is biologically similar to an existing branded drug

bioisosteres - isosteres that specifically preserve electronic and hydrogen bonding characteristics when one
group is exchanged with another

bolus - an amount of drug that is administered, typically intravenously, in a single burst

Caco-2 cells - a cell that is used in cell permeability assays

cell permeability - the ability of a molecule to passively cross cell membranes. High cell permeability
indicates that a molecule will likely be well absorbed from the digestive system.
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central compartment - blood plasma

Cheng-Prussoff equation - an equation that can convert an IC50 value to a Ki value

classical isosteres - isosteres that specifically preserve steric bulk when one group is exchanged with another

clearance (CL) - the removal of a drug from the bloodstream, normally by either excretion or metabolism. The
variable CL has units of either mL/min or mL/min/kg.

clinical candidate - see investigational new drug

combinatorial chemistry - a method, often automated, for making large collections of molecules using varied
building blocks around a molecular scaffold

compartment model - a method for describing how a drug distributes into the various tissues of an organism

competitive inhibitor - an enzyme inhibitor that binds at the active site of an enzyme. Competitive inhibitors
decrease the affinity of an enzyme for its substrate, and therefore increases Km.

composition of matter - a type of patent that covers new chemical substances, especially drugs

compound library - a collection of molecules that can be used to test for biological activity against a protein
target

consensus scoring - the use of multiple scoring methods in an in silico screen to increase the relability of the
resulting hits

Cp - see plasma concentration

CYP - see cytochrome P-450

cytochrome P-450 (CYP) - a superfamily of enzymes, mostly associated with the liver, that perform many
oxidative metabolic reations on drugs

depolarization - the flow of ions across a cell membrane from the side with high concentration to the side with
low concentration

desensitization - an abnormally low response to a drug, often because of downregulation of a receptor

directed combinatorial chemistry - the use of combinatorial chemistry to generate libraries focused upon the
SAR around a lead

distribution - the transport of a drug to and from its site of action by the bloodstream

distribution phase - the time period during which an absorbed drug reaches its full volume of distribution

docking - the computer simulation of a molecule's binding to a target protein

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downregulation - a decrease in receptor expression by a cell in response to a continuous, high-level stimulation

of the receptor

drug-like - a description of a compound with a molecular weight between 400 and 500 g/mol and a lipophilicity
(log P) of near 5

drug product - the entire administered drug. For orally delivered drugs, the drug product includes the drug
substance and all the binders, dyes, and fillers in the pill.

drug substance - the active material within a drug product

drug-target residence time - the half-life of a drug-receptor complex as it equilibrates between its bound and
unbound state

elimination - any process that causes a decrease in the concentration of a drug in the bloodstream. Both
metabolism and excretion are elimination processes.

elimination phase - the period of time after a drug has reached its full volume of distribution and is being
cleared from the plasma

elimination rate constant (kel) - a rate constant that describes rate of elimination for a drug. Elimination rate
constants normally correspond to first-order processes and have units of inverse time.

endogenous ligand - a ligand that is found naturally in the body

enzyme (E) - usually a protein, a biological catalyst that converts a substrate to a product

enzyme-substrate complex (E-S) - the aggregate substance formed by binding between an enzyme and its
substrate

excretion - the removal of waste from the body. For drugs, excretion is normally associated with the generation
of urine by the kidneys through the filtration of blood.

exogenous ligand - a ligand that is not naturally found in the body. Synthetic drugs that bind receptors are
exogenous ligands.

extraction ratio - the fraction of a drug that is removed by an organ based on the plasma concentration of a
drug that enters and leaves the organ

F - see bioavailability

false negatives - compounds that fail to appear active in a screen despite the fact that the compounds do possess
strong binding to the target of interest

false positives - compounds that indicate activity in a screen but are actually not active

fast neurotransmitter - a neurotransmitter that acts as a ligand for a ligand-gated ion channel

first pass effect - the tendency for a significant fraction of an oral drug to be broken down the liver immediately
after absorption from the digestive tract
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fragment - a molecular library compound with a lower molecular weight (150-250 g/mol), fewer non-hydrogen
atoms (10-15), and weaker target binding (Ki ~ 1 mM). Fragments are connected to form hits.

fragment-based drug discovery (FBDD) - a method of discovering hits by linking smaller, weaker binding
molecules (fragments) together to make molecules with hit-like activity

G-protein-coupled receptor (GPCR) - a receptor superfamily that is a very common drug target and affects
many metabolic functions

glucuronic acid - a highly polar molecule that is conjugated with molecules, normally carboxylic acids, to
facilitate excretion by the kidneys

glutathione - a tripeptide that is added to molecules, often phase I metabolites, to detoxify the compound

half-life (t1/2) - the time required for the concentration of a drug to decrease by 50%

Henderson-Hasselbalch equation - an equation that determines the ratio of a conjugate base to its acid based
upon the pKa of the functional group at the pH of the environment

hepatic clearance (CLH) - the elimination of a drug that is attributable to the liver

hepatic portal system - a collection of blood vessels that gathers nutrient-rich blood from the gastrointestinal
tract and transports it to the liver

high-throughput screening (HTS) - a quick, automated method of in vitro screening for determining the
activity of a molecule against a target

hit - a molecule found through screening with a binding affinity of around 1 µM

homologous series - a collection of analogues in which each compound differs by the incremental addition of a
carbon, usually characterized by the lengthening of an alkyl chain

homologue - a specific type of analogue which differs from the lead compound by a single carbon, generally a
CH2 group

hydrogen bonding - an intermolecular force based upon the interaction of a hydrogen attached to an oxygen or
nitrogen with a nitrogen or oxygen lone pair

hydrophobic effect - an entropy-driven force that favors the binding of a hydrophobic drug to a target based
upon solvation changes between the bound and unbound drug

IC50 - the concentration of an inhibitor required to reduce the rate of an enzymatic reaction by 50%

in vitro - Latin for "in glass". In drug discovery in vitro refers to tests that are performed within a test tube or
other artificial container.

in vivo - Latin for "in the living". In drug discovery in vivo refers to the activity of molecule upon a living
organism.
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IND - see investigational new drug

inhibitor - a molecule that slows the reaction between an enzyme and a substrate

intellectual property space - figurative room around a molecular structure that allows the original molecule
and related compounds to be protected through patents because no other patents have been filed on the
compounds

intermolecular force - one of several non-covalent interactions that help bind a drug to its target

interstitial fluid - the liquid that fills the tiny spaces between cells

intravenous (IV) - a method of administration that involves injection of a drug directly into the bloodstream by
way of a vein

investigational new drug - a classification for a molecule that has been approved to be tested in humans but
has not been yet been approved to be marketed. An investigational new drug is also known as a clinical
candidate.

ionic bond - an intermolecular force based upon the electrostatic attraction between two oppositely charged
ions

in silico screening - the process of estimating a molecule's biological activity through a computer
simulation. The screen involves docking a molecule into a target's binding pocket and then scoring the quality
of the molecule-target interaction.

isosteres - functional groups that can be interchanged with one another with minimal impact upon drug-target
binding but significant impact on pharmacokinetics

IV - see intravenous

kel - see elimination rate constant

Ki - the dissociation equilibrium constant of an enzyme-inhibitor complex

lead - a molecule found through screening with a binding affinity of around 1 µM. As the lead is modified and
optimized, its binding will increase to the 1-10 nM level.

lead discovery - a stage in the drug discovery process. Lead discovery involves the screening of molecules to
discovery hits and then selecting the most promising hits as leads.

lead-like - a description of a compound with a molecular weight between 250 and 350 g/mol and a lipophilicity
(log P) of 3 or less

lead optimization - a stage in the drug discovery process. Lead optimization improves the pharmacodynamics
and pharmacokinetics of the lead until they are potentially good enough for the lead to act as a drug.

library - see compound library

ligand - a molecule that binds a receptor

ligand-gated ion channel (LGIC) - a receptor superfamily that controls ion flow across a cell membrane
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ligand efficiency (LE) - a calculated molecular descriptor that estimates the amount of binding energy (ΔGobind)
contributed by each non-hydrogen atom (n) in a molecule. Drugs, hits, and leads typical have a LE value of
−0.30 kcal/mol/non-hydrogen atom or smaller.

ligand lipophilicity efficiency (LLE) - a calculated molecular descriptor that balances a molecule's target
binding against its lipophilicity. LLE values of 3 or higher for a drug, hit, or lead are ideal.

Lineweaver-Burk equation - a linearized form of the Michaelis-Menten equation that gives the relationship
between 1/V and 1/[S]

Lipinski's rules - a set of molecular properties that are simple to determine and useful for predicting whether a
drug will readily diffuse across a cell membrane

lipophilicity (P) - the equilibrium constant that measures the ratio of the concentration of a drug in a mixture of
1-octanol and water. Lipophilicity is often used in a logarithmic form, log P.

magic bullet - a term created by Paul Ehrlich to describe drugs that are able to destroy an invading organism
without affecting the host

maximum tolerated concentration - the maximum concentration (or dose) of a drug that gives a therapeutic
effect without causing excessive adverse effects. The maximum tolerated concentration is at the top of the
therapeutic window.

me-too drug - a drug that is very similar in structure and activity to a molecule that has already been approved
and marketed

metabolism - the chemical breakdown of a drug, generally caused by enzymes in the liver

metabolite - the product of a metabolic reaction upon a drug

Michaelis constant (Km) - a measure of the affinity between an enzyme and substrate. Michaelis constants
carry a concentration unit. The Michaelis constant is used in the Michaelis-Menten equation as well as other
enzyme kinetics relationships.

Michaelis-Menten equation - an equation that models the relationship between the rate of an enzymatic
reaction (V) and the concentration of the substrate ([S])
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minimum effective concentration - the minimum concentration (or dose) require to observe a therapeutic
effect of a drug. The minumum effective concentration defines the bottom of the therapeutic window of a drug.

molecular library - see compound library

molecular space - a hypothetical collection of molecules that fall within a defined set of properties or
characteristics.

morphine rule - a set a structural requirements that is followed by most opiates and opioids. The morphine
rule requires a molecule to contain a benzene connected to a quaternary carbon, then a two-carbon tether, and
finally a tertiary amine.

mutational resistance - the ability of a genetically altered organism to withstand a previously effective
drug. Mutational resistance is frequently encounted in bacteria, viruses, and cancer.

NDA - see new drug application

new drug application (NDA) - a regulatory step in which the FDA reviews clinical data to determine whether a
molecule is safe and effective enough to be approved as a drug

non-classical isosteres - see bioisosteres

noncompetitive inhibitor - an enzyme inhibitor that binds both an enzyme and enzyme-substrate complex. A
noncompetitive inhibitor decreases Vmax without affecting Km.

nuclear receptor - a receptor superfamily that regulates DNA replication and gene expression. Steroids
generally target nuclear receptors.

occupancy theory - a theory in ligand-response relationships that equates the fraction of receptors bound by a
ligand to the fraction of response generated by the receptor

off-label use - the use of a drug in a fashion for which the drug has not been formally tested or approved

oligopeptide - a short string of amino acids with a length too short to be called a proper protein. Oligopeptides
are normally no longer than 20 amino acids in length. Many signal peptides in the body are oligopeptides.

one-compartment model - a simple compartment model in which the drug is assumed to be distributed into
only the plasma

oral bioavailability - the fraction of an oral drug that reaches the bloodstream relative to an IV bolus form of
the drug

pan assay interference compounds (PAINS) - molecules that, because of either a high degree of chemical
reactivity or solubility problems, show up as false positives in screens for activity against a broad range of
protein targets

patent - a form of intellectual property that grants to the holder exclusive rights to an invention for 20 years
from the date of filing

peptidomimetics - a form a lead optimization that attempts to develop a drug with good bioavailability from a
typically poorly available peptide lead
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peptoid - a specific type of peptide isostere that is used to develop a peptidomimetic drug

pharmacodynamics - the branch of medicinal chemistry that focuses the action of a drug at its site of action

pharmacokinetics - the branch of medicinal chemistry that focuses on the movement of a drug from its site of
administration, throughout the body, to its site of action, and out of the body

pharmacophore - the core parts of a molecule that are required for a threshold level of activity

phase I metabolism - oxidative, reductive, and hydrolytic chemical reactions on a drug

phase II metabolism - reactions in which a drug or metabolite is connected to a group (generally very polar) to
either detoxify the compound or assist excretion of the molecule

phenotype - an observable trait of an organism. Symptoms of a disease are an example of a phenotype, and
drugs can modify the symptoms.

plasma - the non-cellular portion of whole blood. Plasma consists of water, electrolytes, signal molecules, and
proteins.

plasma concentration (Cp) - the concentration of a drug within the blood plasma

polymorphism - the ability for most molecules, including drugs, to pack together in multiple, different
arrangements. Each polymorph of a drug potential has different physical properties and is legally considered a
different composition of matter.

pre-clinical trials - a series of standardized toxicity studies in animals to establish the safety of a drug and
provide data for an IND application

primary structure - the simplest level of protein structure. Primary structure describes the order of the amino
acids in the peptide backbone.

privileged structure - a molecular scaffold or part of a scaffold that appears in molecules that have activity
against a range of different targets

prodrug - a drug that is administered in an inactive form and is broken down in the body to reveal the active
form

product - in the context of enzyme kinetics, the material formed from the action of an enzyme on a substrate

promiscuous - a description for a compound that binds to multiple different targets

quaternary structure - the relative orientation of individual proteins within a multi-protein complex

random coil - a type of secondary structure in which the protein backbone has no well-defined conformation

receptor - a protein that acts as a switch for controlling cellular processes

renal clearance (CLR) - the elimination of a drug caused by the kidneys

resolution - a measure of the clarity of an electron density map in X-ray crystallography. Resolution is
measured in angstroms (Å) (1 Å = 10-10 m).
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retroinverso - a specific type of peptide isostere that is used to develop a peptidomimetic drug

Rule of Five - see Lipinski's rules

SAR - see structure-activity relationship

screen - a general term for testing the activity of a drug

secondary structure - localized regions of folding within a protein. Common examples of secondary structure
include the α-helix, β-sheet, and random coil.

sensitization - restoration of a normal response to a ligand, often because of upregulation of a receptor

serum - the fluid left behind after whole blood is allowed to clot. Serum is closely related to plasma, but serum
lacks some of the proteins responsible for clotting.

serum albumin - a protein that tends to bind acidic drugs and makes up between 3 and 5% of the weight of
whole blood

scaffold - a core structure of an active molecule on which different functional groups are substituted. The
scaffold may include general features such as ring systems and tethers connecting ring systems.

scaffold hopping - a technique in lead discovery that involves replacing the scaffold of a promising hit with a
different scaffold. The functional groups on the scaffold are kept the same.

scoring - the use of a computer algorithm to estimate the quality of binding between a molecule and a target
protein

selective optimization of side activities (SOSA) - the practice of discovering new drugs by the modification of
old drugs. Normally, SOSA begins with the screening of a library of varied drugs as a search for hits.

side effect - see adverse effect

slow neurotransmitter - a neurotransmitter that acts as a ligand for a G-protein-coupled receptor

spare receptors - extra receptors in a cell or tissue that need not be bound by a ligand in order to achieve a full
response

structural alert - an awareness that a molecule contains functional groups that frequently lead to drug
toxicity. Two common problematic functional groups are anilines and arylacetic acids.

structure-activity relationship (SAR) - the link between a compound's molecular structure and its
physiological function

substrate (S) - the starting material for an enzymatic reaction. Substrates bind an enzyme at the enzyme's
active site.

sulfa drug - see sulfonamide antibiotics

sulfonamide antibiotics - an early class of antibiotic drugs containing a sulfonamide (SO2N) group
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superfamily - the top level of classification for a receptor. The four superfamilies are ligand-gated ion
channels, g-protein-coupled receptors, tyrosine kinase-linked receptors, and nuclear receptors.

t1/2 - see half-life

target - typically a protein that plays a key role in a biological pathway of a disease. Binding of a drug to the
protein target often influences the pathway and affects the diseased condition.

terminal elimination rate constant - the elimination rate constant than can be observed for a drug that has
reached its full volume of distribution

tertiary structure - the three-dimensional arrangement of secondary structures within a single protein

therapeutic window - a drug's ideal concentration range, which lies between minimum effective concentration
and maximum tolerated concentration

total clearance (CLT) - the sum of all the drug clearing processes in the body

trademark - a form of intellectual property that normally applies to the name brand of a drug. Only a company
who owns a trademark may use the name to market its product.

two-compartment model - a compartment model in which a drug is presumed to equilibrate between the
plasma and a peripheral compartment

tyrosine kinase-linked receptor (TKLR) - a receptor superfamily that is commonly targeted to affect cancer

uncompetitive inhibitor - an enzyme inhibitor that binds the enzyme-substrate complex. An uncompetitive
inhibitor decreases both Vmax and Km of an enzyme-substrate system.

upregulation - an increased expression of a receptor in a cell in response to a lack of stimulation by the

receptor

virtual screening - see in silico screening

Vmax - the maximum rate of conversion that a particular enzyme-substrate system can attain

volume of distribution (Vd) - see apparent volume of distribution

whole blood - the entire contents of blood including water, electrolytes, proteins, signaling molecules, and cells

xenobiotic - an unnatural compound in the body. Most drugs are xenobiotics.

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