Handout 5 - Enzyme Inhibition & Targeting
Handout 5 - Enzyme Inhibition & Targeting CH 405/505
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Popular in Chemistry
This 10 page One Day of Notes was uploaded by Evan Roberts on Friday January 23, 2015. The One Day of Notes belongs to CH 405/505 at University of Alabama - Tuscaloosa taught by Timothy Snowden in Spring2015. Since its upload, it has received 82 views. For similar materials see Medicinal Chemistry in Chemistry at University of Alabama - Tuscaloosa.
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Date Created: 01/23/15
Patrick An Introduction to Medicinal Chemistry 4e Chapter jl Most Common of Enzyme Ihibition 1 Reversible I ComgtH use binds active site thereby preventing substrate from binding very common 2 Noncompetitive Allosteric binds thereby limiting substrate conversion to product but not substrate binding rare 3 Mixed typically Allosteric can bind to E or ES although the binding of either I or S affects the binding of the other very rare 2 Irreversible covalently modi es the active site or allosteric site Suicide SubsWK MechanismBased harmless analog that covalently modi es the active site a er binding and activation by active site residues rare 3 i39Ti n gjf mr 34041 f reversibly bind active site very strongly by mimicking the natural transition state without conversion to product common Copeti ve Inhibition Binding by I must be at least 00 K smngg than S Gleevec tyrosine kinase antitumor agent BCR Abl An aberrant tyrosine kinase BCR Abl is overactive in those suffering from myelogenous leukemia Gleevec binds competitively near the ATP binding site of the tyrosine kinase Mi teric Inhibition Pathways AH binding site distorted so v that substrate binds 7 jinnin or not null J gt little or no product formed Competitive Inhibliinn Ailnsteric active site changes mibrmslim 39Isn built substrate binding and 12 If catalysis 71rduced L f substrate all Illolisriu modulllor binds boll substrate and nihilism mnriiiIilinr hind 39 um inhibitinn 1 Illosmlu si l bclorhnodulnlor p bulb 5mm ml 39 1 silfuiinlin minimising mg u only positions of catalytic residues sir altered catalysis is n nrdnrncl substrate binds Competitive Inhibition Aiiosieric EL 39 slow quot I 39 ullmlrtrin vu Igon39nm nlsinr precluded from binding Product formed I Rifampin Rifadin antibiotic Rifampin noncompetitively inhibits bacterial DNA dependent RNA polymerase Binds at a site 7 acid GAELiquot quotit the RNA polymerase active site and physically blocks formation of a new phosphodiester bond in the growing RNA backbone Irreversible Inhibitan Covalent Bond Irreversible inhibition Natest Inhibit0r likely to be similar in structure to the substrate but in form of an eLeUrrmPt lfc remain Irreversible Inhibitrs Examples m i39 2 Xenieal and L gtflnibB 339 Upcbm mealc bmkdown We we azga mbg Cabswbob web in 51 ac Orlistat I W i J 1L houses gt rstab H r m 4 it u quot39139quot EnHza m i s ihliHGH I r G11H23 M my er w JJW iv in EHH1339 1 a DH Elli NHG HD i 3quot pancrga c upquot Pancreatic llpau 8quot Pa ncroatlc llpau f v A 5 HJQVQFSZ OO side egg9ampng p3quot ConS pmc gt Sun was 3 05 This is GA example due 44 a pkufan I538 s i 536 0423 not WNW in b l n b 10 q Am 1 1 E M Trrulcrs b n 35 mm 430 Waist 1 So 133 CM tom th HP V 7 quot Ei i up c F aw o Pmbffm Salome Substrates Mechanism eased Inhibitors mrquotMattimoi assmt Notes M Pm PM Agents which are converted to irreversible inhibitors by the enzymecatalysed reaction Example Tri uoroalanine as a suicide substrate of alanine transaminase JNIIa Fac ctl Trlfluoroalanlne COQH UNHIBITION GHENHE H H2quot g coz Transamlnase 3GICO2H enzyme 4 I 7 a quot39 I A a N 39 3H3 i Pyrldoxal Nanine Pyrldoxamlne Pvruvlc phosphate monophosphate Add phosphate Reaction misehanism alanine trasam iase Base Enzyme Condensation ll inhibition mechanism alanine transaminase Bun Enzyme Irreversible alkylation Tienilie acid Notes 0 Marketed as a diuretic antihypertensive 0 Agent acts as an unintended suicide substrate on cytochrome P450 enzymes hepatitis Toxicity data hidden by SmithKline executives during clinical trials 1982 criminal charges v 39 TQM wt I Pfeee l qmlg h i aw 39 quot r k I mel tbhkyl its Mrr it Tienilic acid Cyl Iii1 7 Oxidation gt Cyl P450 NADPH Cvl P450 7 Alkylatlon Enzyme alkylaied and Inhlblted Tra sitinuaState Inhibitors E itaniple39 Renin inhibitors 39quoth39b39t quot ACE inhibitors Rai I Angiotensin ll Angiotensinogen Jib Angiotensi 1 enzyme 39 AngiOteHSiquot I 333 liver kidney blood lung blood lARle tissues Notes 0 Renin protease in kidney that hydrolyzes Angiotensinogen First step in ReninAngiotensin System RAS of blood pressure control 0 Angiotensin II causes Vagow gkic on in all tissues raises blood pressure Thus renin inhibitors act as antihypertensives TransitionState Inhibitu Renin mechanism Totrnhodral Imsrmodlitl R can i I l Martin 0 Two aspartyl residues involved in enzymecatalysed reaction 39 T wmwa FM anew involved I39 g f v Campamcl 1 IsmunaState Inhibition m Em hi hn l En mm EMEan 39l39l E39s7 Example Benin inhibitors Aliskiren will rm W5 0 Proteln Reaction Intermedlate 1H EHMez 39 Hydroxveghylene Te39kb m ml Cam wmm mlmIc Notes 0 Aliskiren Tekturna 2007 rstin class drug which contains a hydroxyethylene transitionstate mimic 0 Stable no leaving group present 0 Voluntarily pulled from market in 2011 after showing increased risk of nonfatal stroke and renal complications after longterm use i ine s Determining Type sf a CD quer Nah fnccu39SKNS 17 quot39 no CW Fn Vermi owh Km inst was 1 ans M K S maids 39Tmrmw 11 MI E m ewes m 39l uI39J39imDL39rx 15 83 VimOW 909 SH l 4quot 39i m 14297 1 nonwmggue lm i damages but Km cgm j I 4 C5an I Noncompetitive 1 5W I 62 and 1C5 7 H Hmwuwervgorh Fi r 99 Rug g Jim 6e ravmba E L allquot9 th f aims M 64351111 q Q m GEE Q anwhr o E 1 e a Err quot 1 631 063 K I I 12 Gammon 0003 h v 39 quotquot 39 k ue sthO tOr FCC emers dcr 0quotth K3333 Km 9 F V FIgri J N5 39 jets for useful medications M u 721 Antibacterial age ts Dihydropteroate synthetase transpeptidase 72 Antiviral agents HIV reverse transcriptase HIV protease Viral DNA polymerase An ein ammatory agents Cyclooxygenase quot114 Cholesterol lowering agents HMG CoA reductase 75 Antich i 1quot ts Monoamine oxidase i6 Anticancer agents i Tyrosine kinase dihydrofolate reductase thymidylate synthase aromatase histone deacetylase etc 4 for useful medications 72 En targc ntihypertcnsive agents Renin angiotensin converting enzyme ACE 73 Treatment of male erectile dysfunction Phosphodiesterase Anti g llt agents Xanthine oxidase Anti ulcer agents Proton pump 11 Alzheimers disease Cholinesterases 712 Diuretics Carbonic anhydrase