Med chem II

Med

Medicinal/Pharmaceuti

cal Chemistry

Biological

MedicalPharmaceutical

Science

What is Medicinal/Pharmaceutical Chemistry ? Chem

HISTORY OF MEDICINAL CHEMISTRYMed Chem

What is DrugMed Chem

No drug is totally safe. Drugs vary in the side effects they might have.

The dose level of a compound determines whether it will act a medicine or as a poison.

The therapeutic index is a measure of a drugs beneficial effect at a low dose versus its harmful effects at higher dose. A high therapeutic index indicates a large safety margin between beneficial and toxic doses

The principle of selective toxicity means that useful drugs show toxicity against foreign or abnormal cells but not against normal host cell

why, where, how drug act ?

Drug : Any substance which generate biological response. Good or Bad drugs

Drug TargetMed Chem

Why should chemicals, some of which have remarkably simple structures, have such an important effect on such a complicated and large structure as a human being ?

Cytoplasm

Nucleus Nuclearmembrane

Cell membrane

Chemical Structure of Cell wallMed Chem

Glycoprotein

Lipid bilayer

phosphatidylcholine,

phosphatidylethanolamine,phosphatidylserine,andphosphatidylinositol

Chemical Structure of Cell wallMed Chem

Glycoprotein

O-aglycon

N-aglycon

Glycophorin

Drug targets at the molecular level Med Chem

Proteins : Enzymes Receptors Transport proteins

Nucleic Acids : DNA RNA Biological

10%

Receptor Agonist

12%

Receptor Antagonist

24%

Ion Channel Modulator

8%

Enzyme Inhibitor

38%

Misc8%

Drug targets at the molecular level Med Chem

The equilibrium of a drug being bound and unbound to its target.

Intermolecular bonding forces Med Chem

Electrostatic or ionic bonds

Hydrogen bonds

Van der Waals interactions Dipole-Dipole and ion-Dipoleinteractions

Repulsive interactions

The role of water and hydrophobicinteractions

Electrostatic or ionic bonds Hydrogen bonds Covalent bonds Van der Waals interactions 1.5–2.2 Å 1.0–1.5 Å

Med ChemElectrostatic or ionic bonds

An ionic or electrostatic bond is the strongest of the intermolecular bonds

Closer the charged atoms stronger the bond

Strength of bond depend on environment

Most important initial interaction as the drug enters the binding site

Hydrogen bonds Med Chem

(X, Y = oxygen or nitrogen;HBD = hydrogen bond donor, HBA = hydrogen bond acceptor)

For H bond require an electron-rich hetero- atom (With lone pair) and an electron-deficient hydrogen

The hydrogen bond (5 to 30 kJ/mole) is stronger than a van der Waals interaction, but weaker than covalent or ionic bonds.

hydrogen bond donor (HBD) Has covalently bonded electro +Ve H

hydrogen bond acceptor (HBA) provide electro –Ve atom

hydrogen bond flip-flop



Orbital overlap in a hydrogen bond.

Weak form of sigma bonding

Bond angel 130-180 moderated bond strength90 bond angel week bond

Optimum orientation is where bond angel is 180 where it is strongest bond

Hydrogen bond donor (HBD)/acceptor (HBA)Med Chem

R-F Fluorine is highly electronegative atomWith 3 lone pair of electron….But still weak HBA ?????

Van der Waals interactions Med Chem

Med ChemDipole-dipole

Med ChemIon-dipole interactions

Repulsive interactions Med Chem

Induced dipole interaction between an alkyl ammonium ion and an aromatic ring.

Nicotinic acetylcholine receptor tryptophan residue

https://en.wikipedia.org/wiki/File:Acetylcholine-tryptophane_cation-pi_interaction.png

Repulsive interactions Med Chem

Important to keep molecule at specific distance.

If molecules come too close there molecular orbitals start to overlap and this results in repulsion.

Same group try to repel each other…For example, two charged groups of identical charge are repelled.

The role of water and hydrophobic interactions Med Chem

Ritonavir

The role of water Hydrophobic interactions.Med Chem

Pharmacokinetic issues and medicines Med Chem

Pharmacodynamics is the study of how a drug binds to its target binding site and produces a pharmacological effect

The study of how a drug is absorbed, distributed, metabolized, and excreted (known as ADME in the pharmaceutical industry) is called pharmacokinetics.

‘what the body does to the drug’

‘what the drug does to the body’

Classification of drugs Med Chem

Pharmacological effect analgesics, antipsychotics, antihypertensive, anti-asthmatics, and antibiotics

Chemical structurepenicillin's, barbiturates, opiates, steroids, and catecholamine'sephalosporins, sulphonamides, opioids, and glucocorticoids

target system

target molecule anticholinesterases are drugs which act by inhibiting the enzyme acetylcholinesterase

neurotransmitter

Naming of drugs and medicines Med Chem

Ro31-8959, ABT-538, and MK-639 werecompounds prepared by Roche, Abbott, and Merck

Promising anti-HIV drugs and were named saquinavir, ritonavir , and indinavir

In market brand name (proprietary) Fortovase ®, Norvir ® and Crixivan

Different formulation has different brand name

For generic (non-proprietary) Recommended International NonproprietaryName (rINN), which is usually identical To the name Of The drug.

Protein Structure and function of proteinsMed Chem

The 20 common amino acids found in humans

Primary Structure of proteinsMed Chem

Met-encephalin (one of the body’s own painkillers)

The primary structure is the order in which the individual amino acids making up the protein are linked together through peptide bonds

The secondary structure of proteins Med Chem

The secondary structure of proteins consists of regions of ordered structure adopted by the protein chain.

The -helix The -pleated sheet (antiparallel arrangement)

The secondary structure of proteins Med Chem

Hydrogen bonding in antiparallel and parallel ß-sheets (the arrows are pointing to the C –terminal end of the chain)

The -turn showing hydrogen bonding between the first and third peptide bond.

The tertiary structure of proteins Med Chem

Human cyclindependent kinase 2 (CDK2), where cylinders represent -helices and arrows represent ß-sheets.


Tertiary structure formation as a result of intramolecular interactions.

With the exception of disulphide bonds, the bonding interactions involved in tertiary structure are the same asthe intermolecular bonds


Covalent bonds-disulphides links Ionic or electrostatic bonds

Hydrogen bonds

Van der Waals and hydrophobic interactions

The quartarnary structure of proteins Med Chem

Only proteins that are made up of a number of protein subunits have quaternary structure.