Advanced Medicinal Chemistry Lecture 1: Target Classes PDF

Advanced Medicinal Chemistry Lecture 1: Target Classes Dr Shaymaa Alnaqib  The Drug Discovery Process Target 3 months to Identification 2 years! HTS 3-4 months Active-to-Hit...

Advanced Medicinal Chemistry Lecture 1: Target Classes Dr Shaymaa Alnaqib  The Drug Discovery Process Target 3 months to Identification 2 years! HTS 3-4 months Active-to-Hit (AtH) 3 months Hit-to-Lead 6-9 months (HtL) New Lead Optimisation 2 years Projects (LO) Candidate Drug (CD)  Taxonomy of Biological Mechanisms Receptors - agonists antagonists partial agonists In vivo inverse agonists Effectors Enzymes - inhibitors Ion Channels - openers blockers Protein-Protein - inhibitors  Blockbuster Drugs Lipitor HMG CoA inhibitor Plavix HO O Anti-platelet OH Cl COOMe OH N Enzyme F Receptor N S H N O Thrombosis BMS/Sanofi-Aventis Cholesterol $5.0billion Pfizer $12.0 billion Norvasc Nexium Calcium channel blocker Proton pump inhibitor Cl O O O N O O O O Ion-channel S N N Enzyme N H O NH2 Anti-ulcer Hyper-tension AstraZeneca Pfizer $4.8billion $4.8billion  Biological Mechanisms 2005 Top 50 drugs by Worldwide sales  Enzyme function HN NH2 O NH2 TS NH NH Free Energy iNOS + O2 Free Energy + NO OH OH H2N H2N O O TS E S S P P Progress of Reaction Progress of Reaction # E + S ES E + P Active Site is tailored to bind the transition state for S P Usually, the substrate & inhibitors bind at the active site Allosteric (non-competitive) binding occurs remotely to the active site  Enzyme Inhibition - Four mechanistic categories 1. Competitive inhibition. Inhibitor competes reversibly with substrate for the active site. 2. Uncompetitive inhibition. Inhibitor binds only to the ES complex, leading to EIS intermediates. This is very rare. 3. Non-competitive inhibition. Inhibitor binds non-covalently to sites other than the active site (Allosteric inhibition). Kinetics are complex and partially inhibited enzymes can still turn over substrate.  Enzyme Inhibition - Four mechanistic categories 4. Irreversible inhibition. Inhibitor binds covalently, usually to the active site machinery. Also known as Suicide inhibitors. Examples include MAO inhibitors and -lactamase inhibitors: NH2 NH2 H H p-OH-Ph N S  OH p-OH-Ph N S O O Amoxycillin N turnover HO O HN O CO2H CO2H  OH Scys O OH Clavulanic acid N irreversible  O O O inhibition CO2H  Proteases (proteinases, peptidases) Hydrolytically cleave peptidic amide bonds Endopeptidases cleavage site may be anywhere in the substrate Exopeptidases terminal residue (carboxypeptidase, aminopeptidase) Four Mechanistic Classes Nucleophile pH preference Endo/Exo Serine Ser-CH2OH ~7 endo Cysteine (thiol) Cys-CH2SH ~7 endo Aspartic H 2O 3-6 endo Zinc (metallo) H 2O ~7 endo/exo  Protease Specificity Determined by the binding of substrate amino acid side-chains near the cleavage site Specificity-Pocket nomenclature (Schechter & Berger, Biochem Biophys Res Com, 1967, 27, 157-162) S3 S1 S2’ P3 P1 P2 ' O O substrate H H H Substrate N-terminus N N N C-terminus N N N H H H O O O P2 P1 ' P3 '.. S2 E-XH S1’ S3’ non-prime side prime side  Serine Proteases Thrombin, Tryptase , -Lactamase, Elastase, Chymotrypsin, HCV-NS3 Asp102 Catalytic triad Inhibitors create or mimic O boosts serine nucleophilicity stable tetrahedral O H intermediates N His57 N N H enzyme O -lactams O O Ser195 P1 O H substrate N NHCOR N CF3 H trifluoromethyl P 1' ketones O P1 is the primary O specificity site oxy N -a Arg nion S X /Ly hol O O s ri c e h saccharins  Biological Mechanisms 2005 Top 50 drugs by Worldwide sales  Receptors Receptors are membrane-bound proteins that bind endogenous ligands (usually extracellular) to induce a phsiological effect (usually intracellular) A receptor is often the first step in a long intracellular signalling cascade leading to physiological effects G-Protein Coupled, Seven-Transmembrane Spanning Receptors comprise the majority of known examples extracellular 7TM GPCR intracellular  extracellular loops -adrenoceptor ligand recognition & binding N-terminus I membrane intracellular loops signalling G-protein coupling C-terminus  Binding to Receptors R R* ground-state Excited-state receptor receptor no signal signal Agonist a ligand that binds to, and provokes a signal from a receptor via conformational changes in the excited state Antagonist a ligand that binds to a receptor and induces no signal. Blocks agonist binding. Little conformational change overall ligands can be proteins, peptides or small molecules  Binding to Receptors Agonists & Antagonists bind competitively - beware misunderstandings from binding data without further functional analysis Endogenous agonists often bind weakly (enthalpy driven) Successful antagonists often bind tightly (entropy driven) Inverse Partial Partial Inverse Agonist Agonist Antagonist Agonist Agonist  Biological Mechanisms 2005 Top 50 drugs by Worldwide sales  Ion Channels All of life exists within an electric potential window of less than one volt The membrane potential of most cells is 60-70mV Ion channels regulate passive ion flow through membranes in an electric or concentration gradient Channels are ion selective and comprise groups of glycoprotein subunits in homo- or heteropolymer arrays. Almost no channels have an open rest state Channels are involved in cardiac, neuronal, psychiatric and (?) R&I disorders Which ions? Na+ K+ Ca++ ( Cl- ) hERG (iKr) channel: blockade causes prolongation of cardiac Q-T interval “Long QT syndrome” can lead to sudden death  Ion Channels Channel families are complex, but all channels are either Voltage-gated or Ligand-gated Ligands can be other ions, small molecules or toxins & venoms such as tetrodotoxin, pumiliotoxin, margatoxin & charybdotoxin Blockbuster antihypertensive drugs have emerged from calcium- channel antagonist programmes – Nifedipine, Nimodipine, Isradipine, Amlodipine (NorVasc™)