1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 6: Section

1 © Contents 4.10.Structure based drug design -Strategy & Procedure (16 slides) -Design of Antihypertensives - ACE inhibitors -Carboxypeptidase -Carboxypeptidase mechanism -Inhibition of carboxypeptidase -Lead compounds for ACE inhibitor -Proposed binding mode -Extension and bio-isostere strategies -Extension strategies 4.11.De Novo Drug Design [26 slides]

1 © 4.10 Structure based drug design Procedure Crystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand)Crystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand) Acquire structure by X-ray crystallographyAcquire structure by X-ray crystallography Identify binding site (region where ligand is bound)Identify binding site (region where ligand is bound) Identify binding interactions between ligand and target (modelling)Identify binding interactions between ligand and target (modelling) Identify vacant regions for extra binding interactions (modelling)Identify vacant regions for extra binding interactions (modelling) ‘Fit’ analogues into binding site to test binding capability (modelling)‘Fit’ analogues into binding site to test binding capability (modelling) Strategy Carry out drug design based on the interactions between the lead compound and the target binding site

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1 © Design of Antihypertensives - ACE inhibitors ACE = Angiotensin converting enzymeACE = Angiotensin converting enzyme Angiotensin II - hormone which stimulates constriction of blood vessels - causes rise in blood pressureAngiotensin II - hormone which stimulates constriction of blood vessels - causes rise in blood pressure ACE inhibitors - useful antihypertensive agentsACE inhibitors - useful antihypertensive agents ACE - membrane bound zinc metalloproteinase not easily crystallisedACE - membrane bound zinc metalloproteinase not easily crystallised Study analogous enzyme which can be crystallisedStudy analogous enzyme which can be crystallised 4.10 Structure based drug design

1 © Carboxypeptidase

1 © Carboxypeptidase mechanism 4.10 Structure based drug design Hydrolysis

1 © Inhibition of carboxypeptidase 4.10 Structure based drug design No hydrolysis

1 © Lead compounds for ACE inhibitor 4.10 Structure based drug design

1 © Proposed binding mode 4.10 Structure based drug design

1 © Extension and bio-isostere strategies 4.10 Structure based drug design

1 © Extension strategies 4.10 Structure based drug design

1 © The design of novel agents based on a knowledge of the target binding site 4.11 De Novo Drug Design Procedure Crystallise target protein with bound ligandCrystallise target protein with bound ligand (e.g. enzyme + inhibitor or ligand) (e.g. enzyme + inhibitor or ligand) Acquire structure by X-ray crystallographyAcquire structure by X-ray crystallography Identify binding site (region where ligand is bound)Identify binding site (region where ligand is bound) Remove ligandRemove ligand Identify potential binding regions in the binding siteIdentify potential binding regions in the binding site Design a lead compound to interact with the binding siteDesign a lead compound to interact with the binding site Synthesise the lead compound and test it for activitySynthesise the lead compound and test it for activity Crystallise the lead compound with target protein and identify the actual binding interactionsCrystallise the lead compound with target protein and identify the actual binding interactions Structure based drug designStructure based drug design