Sachin Shinde Department of Chemistry S.M.Joshi College Hadapsar DRUG TARGETS Sachin Shinde Department of Chemistry S.M.Joshi College Hadapsar

Drugs target? Drugs target is any biological system where drugs bind. Generally, a target is a protein molecule although it could be any biological, be it nucleic acid, enzymes ,receptors ,lipid etc. In the past, an animal model of disease could represent a target

Drug-Receptor Interaction Ionic bond H-bond Van der Waals Dipole-dipole /ion dipole Van der waals interaction Phe H-bond Binding site Ser O H ionic bond Asp CO2 Receptor

Hydrophobic region O Asp HO -

ENZYMES E+S ES complex E+P complex P+E Enzymes are biocatalyst, agents that speed up biochemical processes without being consumed themselves. Enzyme act as drug target by inhibiting their action Enzyme inhibitors 1.Reversible/Competitive inhibitors 2. Irreversible inhibitors 3.Allosteric inhibitors E+S ES complex E+P complex P+E

Competitive Enzyme inhibitor

Competitive Inhibitors

Increased Blood Vol. Rise in BP Kidney (Adrenal cortex) Vasoconstriction Na+ & water retention Kidney (Adrenal cortex)

ACE inhibitors Captopril (Capoten) Lisinopril (Prinivil) Enalaprilat Enalapril (Vasotec) Fosinopril (Monopril) Quinapril (Accupril) Ramipril (Altace) Enalaprilat Enalapril

Anti inflammatory drugs Aspirin, Ibuprofen,Nimesulide,Diclofenac. etc

Irreversible Enzyme inhibitor OH OH X O X

Non competitive (reversible) allosteric (open) ENZYME Induced fit Binding site unrecognisable Binding site ACTIVE SITE (open) ENZYME Allosteric site Antagonist drug binds reversibly to an allosteric site Intermolecular bonds formed between drug and binding site Induced fit alters the shape of the binding site Binding site is distorted and is not recognised by the messenger

Receptors Receptors are proteins either embedded in cell membranes or in the nuclei of cell

Chemical Messengers Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body Receptor Nerve Nucleus Cell Messenger Cell Nerve Response

5. Signal transduction Control of ion channels Receptor protein is part of an ion channel protein complex Receptor binds a messenger leading to an induced fit Ion channel is opened or closed Ion channels are specific for specific ions (Na+, Ca2+, K+, Cl-) Activates or deactivates enzyme catalysed reactions within cell Hydrophilic tunnel Cell membrane

5. Signal transduction Control of ion channels Binding site Receptor Messenger Cell membrane Cell membrane Induced fit ‘Gating’ (ion channel opens) Five glycoprotein subunits traversing cell membrane Cationic ion channels for K+, Na+, Ca2+ Anionic ion channels for Cl-

G coupled protein receptor

Ligands: Peptide hormones

Agonists

10. Agonists Agonist binds reversibly to the binding site Similar intermolecular bonds formed as to natural messenger Induced fit alters the shape of the receptor in the same way as the normal messenger Receptor is activated Agonists are often similar in structure to the natural messenger E Agonist R E Agonist R Agonist R Induced fit Signal transduction

Regulation of cardiac myocyte Ca2+ flux Regulation of cardiac contractility by β-adrenergic receptors

6. Antagonists Antagonist binds reversibly to the binding site M An An R E R Antagonist binds reversibly to the binding site Different induced fit means receptor is not activated No reaction takes place on antagonist Messenger is blocked from the binding site Increasing the messenger concentration reverses antagonism

Design of Antidepressants SSRIS citalopram (Celexa) escitalopram (Lexapro) fluoxetine (Prozac) fluvoxamine (Luvox)) sertraline Fluoxetine Sertraline

Amine neurotransmitters are either degraded (metab) or reuptaken MAO Mito COMT

NUCLIC ACIDS AS DRUG TARGETS DNA RNA We shall first consider the drugs that interact with DNA. 1.Intercalating agent 2.Alkylating agents 3.chain terminators 0ther Possible mechanisms: Incorporation in DNA or RNA; misreading Inhibition of DNA polymerase Inhibit of enzymes involved in pyrimidine / purine biosynthesis

Intercalating drugs acting on DNA Intercalating agents are compounds that insert themselves between the bases of the DNA helix . This insertion causes the DNA helix to partially unwind at the site of the intercalated molecule. This inhibits transcription, which blocks the replication process of the cell containing the DNA.. Inhibition of cell replication can lead to cell death

Drugs whose mode of action includes intercalation are the antimalarials quinine and chloroquine, the anticancer agents mitoxantrone and doxorubicin, and the antibiotic proflavine. In each of these compounds it is the flat aromatic ring system that insrts between the DNA base pairs is responsible for the intercalation.

Alkylation of DNA

Chain termination

Antiviral Drugs Figure 20.16a

More recently, a series of other nucleoside analogues derived from these drugs and active against herpesviruses have been developed:                                                                                     

Role of RNA inside the Cell According to traditional central dogma of genetics RNA is the intermediate carrier of genetic information between DNA and Protein. DNA RNA PROTEIN Transcription Translation

Lipids Generally drug interacting with the lipids which are located in the cell membranes. Lipids act as drug target by disrupting the structure Of cell membranes. Drugs acting on cell membrane lipids Anaesthetics and some antibiotics Action of amphotericin B (antifungal agent) - builds tunnels through membrane and drains cell of vital ingredients and causes death. Fungi have Ergosterol as membrane lipid as compared to Cholesterol found in humans and thats the reason for some selective toxicity Hydrophilic Hydrophobic region

Polar tunnel formed Escape route for ions

Thank You

Assigned Reading An Introduction to Medicinal Chemistry by Graham Patrick,. Medicinal chemistry an introduction by Gareth Thomas