Lecture-4 NRK

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Revision Tutorial Dr. Neil KITTERINGHAM Dept. of Pharmacology LECTURE 5 : Pharmacophores : Definition and identification LECTURE 4: Chemical bonds involved in drug action LECTURE 6 : Stereochemical aspects of drug action LECTURE 7 : Conformational aspects of drug action : Introduction to PHARMACOLOGY “the Chemical Basis of Pharmacology”

Formative exercise:

Formative exercise

Formative exercise:

Formative exercise Computer-aided learning exercise Go through tutorial programme in your own time Complete MCQ and hand in score sheet by Monday 19 th April Related tutorial 17 th May 11.00pm

How do drugs work?:

How do drugs work? Some drugs have non-specific effects related to their physicochemical characteristics Antacids Laxatives Purgatives Diuretics Most drugs have specific effects related to their chemical structure , as a result of binding to specific targets

Drugs:

1. Drug s Usually organic Frequently cyclic e.g. paracetamol aspirin (acetyl salicylic acid) O H N H C O C H 3 O C C H 3 O C O O H C 2 H 5 OH alcohol Li, Au Al(OH) 3 morphine Drugs

What targets do drugs bind to?:

What targets do drugs bind to? Some drugs, such as those used to treat cancer, bind to DNA Some drugs, such as those used to treat bacterial infections, bind directly to bacteria Most drug targets are HUMAN PROTEINS

Proteins as Drug Targets:

A protein is composed of a long chain of amino acids Proteins as Drug Targets Alanine Glycine Leucine Valine Glutamic acid Aspartic acid Lysine Histidine Phenylalanine Serine Cysteine Asparagine

Proteins as Drug Targets:

Chains are often hundreds of amino acids in length Amino acids join by peptide bonding Proteins as Drug Targets NH 2 -Asp-Phe-Val-His-COOH or DFVH

Proteins as Drug Targets:

Protein does not exist as a long “chain” of amino acids The chain folds up into a 3-dimensional “ball” 3D Structure of a protein Proteins as Drug Targets

Proteins as Drug Targets:

Based on chemical properties of the individual amino acid residues Some amino acids are hydrophobic (“water-hating”) Some amino acids are hydrophilic (“water-loving”) Hydrophobic amino acids try to stay together – so do hydrophilic ones Some amino acids can form “cross-links” with others How does a protein decide what its 3-dimensional shape will be? Proteins as Drug Targets

Proteins as Drug Targets:

“ hydrophobic” – dislikes water Used interchangeably with “ Lipophilic ” means “likes fat” Some amino acids are “hydrophobic” Proteins as Drug Targets e.g. Glycine No ionisable groups in the side chain Alanine Alanine Glycine Leucine Valine Phenylalanine

Proteins as Drug Targets:

“Hydrophilic” means “likes water” Used interchangeably with “lipophobic” – dislikes fat Some amino acids are “hydrophilic” Proteins as Drug Targets e.g. Aspartic acid Ionisable group in the side chain Glutamic acid Aspartic acid Lysine Histidine Serine Asparagine

Proteins as Drug Targets:

Cysteine can cross-link with another cysteine through an interaction between the –SH groups Important for protein folding Some amino acids can form cross-links Proteins as Drug Targets Cysteine S S SH SH

Target Molecules:

Target Molecules Host targets receptors ion channels enzymes carrier molecules (transcription factors/nucleic acids) Foreign targets Microbes cell walls enzymes

500 current drug targets:

500 current drug targets Proteins/peptides~ 95% Structures known only for a small group

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DRUG small chemical ~ 200 - 500 Da TARGET MOLECULE Protein ( enzyme, receptor ) ~ 10,000 – 200,000 Da Altered action Therapeutic effect Molecules in Pharmacology

Receptors:

receptor response nature of chemical interaction AFFINITY SPECIFICITY Receptors

Chemical Bonds Involved in Drug Action:

Chemical Bonds Involved in Drug Action Type Energy (kJ/mole) 150-600 20-40 8-20 3-15 5-25 0.5-5 Covalent bond Ion-ion Ion-dipole Dipole-dipole Hydrogen Van der Waals Relationship between strength and distance 2 3 4 5 8 - 1/d 1/d 1/d - 1/d 1/d 1/d 1/d 1/d 3

Chemical Bonds Involved in Drug Action:

Chemical Bonds Involved in Drug Action Type Energy (kJ/mole) 150-600 20-40 8-20 3-15 5-25 0.5-5 Covalent bond Ion-ion Ion-dipole Dipole-dipole Hydrogen Van der Waals Role rare Initial attraction ‘goodness’ of fit }

Chemical Bonds Involved in Drug Action:

Bonds between LIGAND and AMINO ACIDS in receptor binding site Several types – act simultaneously Rarely covalent, usually reversible Transmitters and Drugs Chemical Bonds Involved in Drug Action OVERALL STRENGTH AFFINITY GEOMETRY SPECIFICITY

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