Handout 4 - Enzymes as Drug Targets
Handout 4 - Enzymes as Drug Targets CH 405/505
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This 12 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 97 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 5e Enzyme Fuml ntals Chemical reactions at physiological pH and temperature are too slow to support life y39 quotif Ratelimiting r Reactlon Enzyme I Iiquot 1 1 Binding Commonly multiple chemical steps 2 Te Active Site Hydrophobic hollow or cleft on the enzyme surface 0 Accepts reactants substrates and cofactors Contains amino acids which bind reactants substrates and cofactors catalyse the reaction Active site Active Slte Substrate Biudm Substrate 39 Induced t Notes 0 Active site is nearly the correct shape for the substrate 0 Binding alters the shape of the enzyme chm 0 Binding also fgmbmaes 39i39mn39fs xj39gsu 3 in the substrate 0 Substrate becomes for reaction Bonding forces 0 Ionic Hbonding 0 van der Waals Emailla Binding of pyruvie acid LDH Possible interactions HBond van der Waals I nailing forces Induced t Active site alters shape to maximise intermolecular bonding lgllmuniisii iianngi nggIlI39l lri39iliilili IlilIlliiEiiiiiEEAEHIEE EIHIIIIllil llllIlllili ii i i l 39 m IliIiililiiliiquotii ll lllii iiliillll Induced t Intermolecular bonds not optimum Intermolecular bond lengths optimised length for maximum bonding Susceptible bonds in substrate strained Susceptible bonds in substrate more easily broken ms SWIVIH or Cl slebili L WEHM Catalysis mechanisms 0 Histidine s9 sz JPN h Nonionised lonised Acts as a basic catalyst Acts as an acid catalyst proton 39sink39 proton source LSerine LCysteine 4 Catalysis w n chino 39 sin acidbase amp nucleophilic catalysis C ntc r wglm sitHag ofscrinc histidime and aspartate a k 7 a 5 E FILC E iiin H1quot j Ft mm lt 1 n we I r await Catalysis chanisms fur EEEMIJK inf c 7 PrutalianHH Prnteln C I 1y ITH l r ps i n x MEchauiism Em thymequot 1 9 ll 7 ll O J I E NH Pr t lm Pratem 4 Catalysis mechanisms Mechanism fur fhym trypsin III 9 cm Fmtelm 7 GEEHH Pmt in C I 1y I nolrry39 psi I ii Menhanism far thymutwpsin Protein Catalysis lmnisms Machinism far chyma quot Pmtain 7 j 7 Catalysis mechanisms Mechanism fur thymotijrpsin 7 H Protein 26 Case Si udkL I S l aHnS Cf39 i Catalysis L Vquot M Mechanism for e hi39jmutrypsin O O OH Protein ES 2 ES EP EP Notes 0 Binding interactions must be strong enough to hold the substrate suf ciently long for the reaction to occur 0 Interactions with product must be 7 Weak enough to allow it to depart quickly 0 Designing molecules with stronger binding interactions results in enzyme 139 Hawker which block the active site Regulation oiquot Red woe a 5 X Transport proteins or upstream enzymes MUCL LE 77 H E lt5 H c m Repress gene expression mRNA or translation 0quot EMT ff 01 SON 6 a U 4quot 5 Deactlvate Enzyme 3 8 l allos39ccrf C inhibition code t eg kinase inhibition cell messenger binding inhibition indirect quot mes Allosteric Inhibition Active site Am Sit unrec lsable Induced t A v 2 binding site Allosteric Inhibitor or activator collectively called modulators Inhibitor binds mlw to an allosteric binding site 0 Induced fit alters the shape of the Mullquot 950 E g enzyme at r 0 Active site is distorted and is not recognised by the substrate 3 mbla w 0 Increasing substrate concentration not reverse inhibition Allosteric inhibitor is not similar in structure to the substrate Regulation of Inhibition Biosynthetic pathway i I 999 quot391 P f P 39 P Inhibition YouBbcQL control Notes Allosteric regulation is most common in multienzyme pathways 0 Enzyme is controlled by the concentration of the nal product of the pathway andor a product from a Sapm lt up 441 A Other products from the same pathway do not inhibit enzyme Because allosteric binding is reversible when P decreases the enzyme activity dunL715 assuming a feedback product from a different pathway is not involved ulation of Enzymes Phospho Control External signals can regulate the activity of enzymes eg neurotransmitters or hormones Second messenger produced initiates a signal cascade which activates enzymes called protein kingses 0 Protein kinases powwow a target enzymes at Y S or T to activate or deactivate them roln phminonigs dephosphorylate producing opposite effect I I Surface ccll finiep39inr 1 Hormone eg epinephrine insulin glucagon First messenger Miehael s Mente Graphical of KM Rate of i quot ff39 fr39 ratemax Vmax reaction 39 kmtughot ratemax u I E KM 51 Product I Ratelimiting Fast I Reatctie I Under saturation kineticsquot kcat k3 assuming k3 is much lower than k1 or k2 KM KD lg Ifwlgzytk S 05Vmaxassuming no afxosmt control Typically1 Ojitoji171fifor most enzyme substrates Indicates how we a substrate binds lower is better Compound with largest kcatKM speci city constant is considered the best substrate for a given enzyme Kinetics Lineweavere u rke Plats 1Vo Slope KMVmax Intercept 1KM Intercept 1 me o 1S Figure 012 lluhemlum Seventh Idlclen O 2012 W H freemen end Company