Points to remember from Med chem IV

• Transport proteins, enzymes, and receptors are common drug targets.

• Transport proteins transport essential polar molecules across the hydrophobic cell membrane.

• Tubulin is a structural protein which is crucial to cell division and cell mobility.

• Many cell processes depend on the interactions of proteins with each other.

Enzymes are proteins that act as the body’s catalysts by binding substrates and participating in the reaction mechanism.

The active site of an enzyme is usually a hollow or cleft in the protein. There are important amino acids present in the active site that either bind substrates or participate in the reaction mechanism

Binding of substrate to an active site involves intermolecular bonds.

The amino acid histidine is often present in active sites and acts as an acid/base catalyst. Glutamic acid, aspartic acid, and tyrosine also act as acid/base catalysts in some enzymes

Cofactors are metal ions or small organic molecules (coenzymes) which are required by many enzymes. Coenzymes can be viewed as the body’s chemical reagents

Medicinal Chemistry V Enzyme Structure and Function

Enzyme as Catalyst

How do enzyme catalyze reactions ?

Active site of Enzyme

Isozyme

Enzyme kinetics

Enzyme kinetics

Enzyme as Catalyst : Activation Energy

Where E is the activation energy and A is the frequencyfactor.

Receptors : structure and function

• Receptors are proteins which are, by far, the most important drug Targets in medicine.

• They are implicated in ailments such as pain, depression, Parkinson’s disease, psychosis, Heart failure, asthma, and Many other problems

• In biochemistry and pharmacology, a receptor is a protein molecule usually found embedded within the plasma membrane surface of a cell that receives chemical signals from outside the cell.

• Cell surface receptor, a receptor on the outer surface of a cell membrane, that takes part in communication between the cell and the outside world

• Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse

• Nuclear receptor, a receptor found within cells that is responsible for sensing steroid and thyroid hormones and certain other molecules

• Immune receptor, a receptor that occurs on the surface of immunocytes and binds to antigens

How do enzymes catalyzed reactions ?

Enzymes provide a reaction surface and a suitable environment.

Enzymes bring reactants together and position them correctly so that they easily attain their transition state configurations.

Enzymes weaken bonds in the reactants.

Enzymes may participate in the reaction mechanism.

Enzymes form stronger interactions with the transition state than with the substrate or the product.

The process of enzyme catalysis

The active site of an enzyme

Binding - amino acid residue is involved in binding the substrate or a cofactor to The active site;

Amino acids present in the active site can have one of two roles:

Catalytic- Amino acids present in the active site can have one of two roles:

Substrate binding at an active site

The interactions which bind substrates to the active sites of enzymes ?

pyruvic acid - substrate for lactate dehydrogenas

The catalytic role of enzymes

Mechanism of Enzyme catalysis

Binding interactions

Acid/Base catalysis

Nucleophilic groups

Cofactors

Binding interactions

Not only enzyme but substrate to change its shape…..

Enzyme stabilizes transition state more than substrate…..

e.g. Pyruvic acid interact with active site of lactate dehydrogenase viaH bond, ionic bond and one van der Waals interactions

Fischer’s lock and key hypothesis

Koshland’s theory of induced fit

Acid/base catalysis

Acid/base catalysis is often provided by the amino acid histidine, which contains an imidazole ring as part of its side chain.

3-hydroxy-3-methyl-glutaryl-CoA reductase HMGR

NH3

O

HO

O

O

L-glutamic acid

17β-Hydroxysteroid dehydrogenases

Tyrosine

Nucleophilic groups

The amino acids serine and cysteine are present in the active sites of some enzymes. These amino acids havenucleophilic residues (OH and SH respectively) which are able to participate in the reaction mechanism.

Hydrolysis of peptide bonds catalyzed by the enzyme chymotrypsin.

Cofactors

Many enzymes require additional non-protein substances called cofactors for The reaction to take place.

Prosthetic groups

A knowledge of how the coenzyme binds to the active site allows the possibility of designing enzyme inhibitors that will fit the same region

SN+

NH2

NN

Cl-PO

O OHOH

OPO

OH

THIAMINE PYROPHOSPHATE

N

OH

O

PO

OOH

OH

PYRIDOXALPHOSPHAT

HS

HN

HN

HO

OP O

P O

OPHO

HOO

OH

NN

N N

NH2

O

OH

O

OH

O

OO

COENZYME A

OH

NHO

HHN

H S

O

Biotin

Naming and classifi cation of enzymes

The name of an enzyme reflects the type of reaction it catalyzes, and has the suffix -ase to indicate that it is an enzyme. For example, an oxidase enzyme catalyzes an oxidation reaction.

Regulation of enzymes/ allosteic binding

Enzymes are controlled by agents which caneither enhance or inhibit catalytic activity

Regulation of enzymes/External

Phosphorylation

Epinephrine, also known as adrenaline, is a medication, hormone and neurotransmitter.

Regulation of enzymes/External

Cyclic adenosine monophosphate

 adenylate cyclase  adenylate cyclase

Regulation of enzymes/External

Isozymes

Enzymes having a quaternary structure are made up of a number of polypeptide subunits. The combination of these subunits can differ in different tissues. Such variations are called isozymes . For example, there are five different isozymes of mammalian lactate dehydrogenase (LDH) tetrameric enzyme made up of four polypeptide subunits.

HHHH, HHHM, HHMM, HMMM, and MMMM