International University of Africa

Faculty of PharmacyMedicinal Chemistry

MCHM 311Siddieg Omer Elsiddieg, M. Sc,

B. Sc (Honors)

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Laboratory, Homework, Assignments, and Term Paper

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Class ContentsIntroduction to Medicinal ChemistryPhysicochemical Properties of Drugs in

Relation to Biological ActivitiesReceptors: Structures and FunctionsPrinciples of Drug DesignDrug MetabolismFactors Influencing Drug MetabolismToxic Effects of Drug Metabolism

What Is Medicinal Chemistry?

“ A chemistry-based discipline, involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification, and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure activity relationships (SARs), the relationship between chemical structure and pharmacological activity for a series of compounds.”

“is the applied science that is focused on the design (or discovery) of new chemical entities (NCEs) and their optimization and development as useful drug molecules for the

treatment of disease processes.”

In achieving this mandate, the medicinal chemist must:

Design and synthesize new molecules. Ascertain how they interact with biological

macromolecules (such as proteins or nucleic acids).

Elucidate the relationship between their structure and biological activities.

Determine their absorption and distribution throughout the body.

Evaluate their metabolic transformations.

Medicinal Chemistry is Interdisciplinary:

Theoretical ChemistryOrganic ChemistryAnalytical ChemistryMolecular Biology PharmacologyBiochemistry

Bottom Line:Design and synthesis of new drugs

How Did we Arrive Here?A brief History of Medicinal Chemistry

Ideas, tools, and knowledge that advanced contemporary medicinal chemistry

Drugs of AntiquityFats, Oils, honey, wax and milk were used Mud, and Salts were used for wound dressingFried Ox Liver for blidness

The Middle AgesThe use of Antimony salts as alixirs

The Nineteenth Century Expansion of chemical knowledgeFocus on finding the active ingredients in the

plants and animal remedies (e.g. isolation of morphine).

Increased use of pure substancesBirth of pharmaceutical industry

The twentieth CenturyDomagk discovery of sulfa drugs (Prontosil)Discovery of penicillinModern medicinal chemistry

What are Drugs?

A drug molecule possesses one or more functional groups positioned in three-dimensional space on a structural framework that holds the functional groups in a defined geometrical array that enables the molecule to bind specifically to a targeted biological macromolecule, the receptor.

The structure of the drug molecule thus permits

a desired biological response, which should be beneficial (by inhibiting pathological processes) and which ideally precludes binding to other untargeted receptors, thereby minimizing the probability of toxicity.

The framework upon which the functional groups are displayed is typically a hydrocarbon structure (e.g., aromatic ring, alkyl chain) and is usually chemically inert so that it does not participate in the binding process. The structural framework should also be relatively rigid (“conformationally constrained”) to ensure that the array of functional groups is not flexible in its geometry, thus preventing the drug from interacting with untargeted receptors by altering its

molecular shape

To be successful in countering a disease process, however, a drug molecule must have additional properties beyond the capacity to bind to a defined receptor site.

It must be able to withstand the journey from its point of administration (i.e., the mouth for an orally administered drug) until it finally reaches the receptor site deep within the organism (i.e., the brain for a neurologically active drug)

Receptor macromolecules are frequently proteins or glycoproteins. Certain properties must be present if a macromolecule is going to have what it takes to be a druggable target. The receptor macromolecule must be intimately connected with the disease in question, but not integral to the normal biochemistry of a wide range of processes.

A drug is most effective when its structure or a significant part of its structure, both as regards molecular shape and electron distribution (stereoelectronic structure), is complementary with the stereoelectronic structure of the receptor responsible for the desired biological action.

The section of the structure of a ligand that binds to a receptor is known as its pharmacophore.

Drug Discovery and Design Know what properties turn a molecule into a

drug

Know what properties turn a macromolecule into a drug receptor.

Know how to design and synthesize a drug to fit into a receptor

Lead Compounds

What are the lead compounds? Promising starting compoundsHow to identify them? Rational drug design Random high throughput screening, Focused library screeningHow to optimize them?QSAR studies

Sources of Drugs and Lead CompoundsNatural Sources:

Are still important sources of lead compounds and new drugs.

The large diversity of potential natural sources in the world makes the technique of random screening a rather hit or miss process.

Eethnopharmacology offers the basis of a more systematic approach.

Identifying a material containing an active compound:

ExtractionPurification Assessment of the pharmacological activity

The isolation of useful quantities of a drug from its land or sea sources can cause ecological problems.

Yew Tree

Drug Synthesis Start with the pathology of the diseased

state and determine the point where intervention is most likely to be effective.

Lead compounds are then synthesized and their pharmacological activity evaluated.

Analogues are produced and screened. Labor intensive

Me-Too DrugsA way to cut the cost of producing drugs

By synthesizing and marketing drugs that are similar in structure and activity to those produced by competitors.

Classification of Drugs Drugs are classified in a number of different

ways depending on where and how the drugs are being used.

Chemical structures Pharmacological Action (site of action,

targeted system).

Drugs with similar chemical structures may have different pharmacological activities.

Routes of Administration

Pharmacokinetics PhaseThe pharmacokinetic phase of drug action

includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug.

Absorption Absorption is the passage of the drug from

its site of administration into the plasma after enteral administration.

It involves the passage of the drug through the appropriate membranes.

Good absorbance requires that a drug molecule has the correct balance between its polar (hydrophilic) and

nonpolar (hydrophobic) groups.

Drugs that are too polar will tend to remain in the bloodstream, whilst those that are too

nonpolar will tend to be absorbed into and remain within the lipid interior of the membranes.

Distribution Distribution is the transport of the drug

from its initial point of administration or absorption to its site of action.

The main route is the circulatory system; however, some distribution does occur via the lymphatic system.

MetabolismDrug metabolism is the biotransformation of

the drug into other compounds referred to as metabolites.

These biotransformations occur mainly in the

liver but they can also occur in blood and other

organs such as the brain, lungs and kidneys.

Elimination Elimination is the collective term used for

metabolic and excretion processes that irreversibly remove a drug from the body during its journey to its site of action. It reduces the medical effect of the drug by reducing its concentration at its site of action.

Slow Elimination Rapid Elimination

Bioavailability of Drugs The bioavailability of a drug is defined as

the fraction of the dose of a drug that is found in general circulation It is influenced by such factors as ADME.

Bioavailability is not constant but varies with the body’s physiological condition.

Pharmacodynamic Phase Pharmacodynamics is concerned with the

result of the interaction of drug and body at its site of action, that is, what the drug does to the body.

A drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is complementary to the steroelectronic structure of the active site or receptor.

THE END