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Statins and Cell Receptor Drug Targeting

by: Evan Roberts

Statins and Cell Receptor Drug Targeting CH 405/505

Marketplace > University of Alabama - Tuscaloosa > Chemistry > CH 405/505 > Statins and Cell Receptor Drug Targeting
Evan Roberts
GPA 3.57
Medicinal Chemistry
Timothy Snowden

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About this Document

The first of these filled-in handouts covers the biological roles of cholesterol & lipoproteins, and also gives a detailed overview of the manipulation of this cycle with Type I and Type II statins...
Medicinal Chemistry
Timothy Snowden
Class Notes
25 ?




Popular in Medicinal Chemistry

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This 46 page Class Notes was uploaded by Evan Roberts on Friday January 30, 2015. The Class Notes belongs to CH 405/505 at University of Alabama - Tuscaloosa taught by Timothy Snowden in Spring2015. Since its upload, it has received 145 views. For similar materials see Medicinal Chemistry in Chemistry at University of Alabama - Tuscaloosa.

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Date Created: 01/30/15
CM Chylomicron 39 7 CMR Chylomicron Remnants 1 39 39 TAG Triacylglycerol c Cholesterol Gall Bladder a CB Cholesterol ester LPL Lipoprotein lipase Cholesterol and Lipopmteius Ho 1 Nut Liver packages cholesterol and lipids in v L D L 5 f As VLDLs lose lipids they become f LDLS which continue to carry insoluble cholesterol and some triglycerides R SANS in liver remove cholesterol Some LDLcholesterol can invade arterial walls get oxidized and attract macrophages to form foam 3 l lg plaques that can cause atherosclerosis clot formation stroke and heart attack Liver creates Hm 5 7 that carry cholesterol removed from cell membranes or foam cells and transport antioxidant lipids that protect arterial walls from oxidizing LDLcholesterol Mortality is associated with high I L b L or low ll 7 l 1 ll f quotelf for Target 3 HMOGahradunmg V CoA Equot 1 VA SHMGCoA 2NADPH 2mpe RMevalonate Inhibit biosynthetic pathway to cholesterol Overi30 enzymes involved in pathway Prevent synthesis of cholesterol within cells but not grave 3mm Targets the enzyme catalyzing the L rec Ugh39m leiquot 31 HMOcof n the biosynthetic pathway 3hydroxy3methylglutarylcoenzyme A reductase aka HMGR or HMGCoA reductase oA binding interactions ionic I e e HaN LyITas Catalytie mechanis a Ewe Hiya Em H 39 a Hisass Ha I 5H Hag5 H a We Him 39 a H MevaldyICOA V E H from NADPH Notes oLys His Glu and Asp are involved in reaction mechanism oHistidine acts as acid catalyst Lys691 stabilises negatively charged oxygen ofmevaldyl CoA and eradmcd ml MUN dig jeading to it Glu559 liviEM Illsylv E l l quot Eagle s tit5h Hbond a H39bmd lo 1quot quotquot from NADPH NM Glutamic acid acts as an acid catalyst Mimosa Lyie E Bil err M NH H I H 39 HE Hbond JL SH CoA H H Mevaldehyde liyis gl I UquotEEQ H as a H m quot H quot 3 gquot 393 H Hbond OH RlH H Mevalonate Aspartate residue shares proton with Glu559 and stabilizes Lys691 Glu559 39 M Stunn alin mummytosrin j Pravastatin PlenumFm cm241 Ich ic Nu m Lovastatin revolutionised treatment of hypercholesterolaemia natural product discovered in 1978 FDA approved in 1987 0 Simvastatin introduced in 1988 as zaumi Sal MMHL 3931 Ofiuve of lovastatin 1 u Pravastatin semisynthetic analog of mevastatin the rst HMGR inhibitor isolated from fungi in 1970 reached market in 1991 wt I Statius HG f Polar 39head39 Hydrophoblc molety calln rln General structure of type I statins contains a polar head and a hydrophobic moiety including a decalin ring Lovastatin and Simvastatin are prod FUiQO S ring is hydrolysed to give the polar head in ngdq lameoun ini SMwS if He QC no 51305c cq Ciruj whoa wag attu umcj in LPIPica y m Haw 39EEES meme where lactone Polar 39head39 Hydrophobic molety n iiiqrrmgwnh grsmm Dacalln rlng Dimdwnmgm nf 391 I 0 Various gust Difficult hr a ymagmg ig nWMSFEL ss Ellynng ALE rirf39l Lili l i i Ccrlv tl n 53m If s an lEg 8 IM 1 3 39 390 I39M dig Names 39 Synth etic agents 0 Contain larger MA ro ph ob i c 41m moiety with no S Jrereg a mm I Statins Rf i le l il Y Hmme I ICE 539 3 st 7 mtgum 39ElHlj v quot n 1 II 0 S LiQonaunt Q Lair jfoUPS QM inc eccng IQSoL in SLnSfHVlJ LI Structures share a number of similar features me ic AH oRosuvastatin is the most potent related to sulfonamide group Cerivastatin is the most hydrophobic withdrawn in 2001 oPravastatin and rosuvastatin are the least hydrophobic statins oPitavastatin shown to raise HDL levels Fewer side effects w type 2 diabetics II Sta ns Statins with less Mom mb c character target liver cells and have reduced 3 3 Ac ej39sleCirS A less prone to passive diffusion Side effects thought to be due to inhibition of HMGR in mU bd Obi 9 that require ubiquinone ie CoQ10 Common side effect is myalgiamyopathy muscle paincramping Rhabdomyolysis severe muscle toxicity which can be fatal Cerivastatin withdrawn in 2001 due to rhabdomyolysis and 50 fatalities I I CoA lm D i HMG SCOA Hydrophobic group Statins Competitive inhibitors of HMGR I SCoA Pam lmcl 95 mm gig mimics the natural substrate HMGSCoA Brigg oHydrophobic moiety forms additional hauling MW EU i go oBinds stronger than natural substrate but does not undergo reaction no leaving group quot 1 QHIVEEEB Wham H lm Hi Hbonzda 7quot SH CoA H H Mevaldehyde Transition strata of i would resemble ltigsanrMHngbLbLmr Mm mu m ims ul srl in I Not Statins likely resemble the transition state of the rst stage of the reaction mechanism thus F Uem ble 39W SEHOO SPAit Mm 105 a interactions 391Idln le bond F 59 lquotw39li HHquotA mutt3 SOFSGS Not Polar head group binds in manner similar to substrate Hydrophobic moiety does not bind to the pocket for SCoA oEnzyme is exible and alters shape to accommodate statins Hydrophobic pocket is created to bind the hydrophobic moiety Biing interacting 1 DH flownWham subsllriir nmuewni ve39rrgfgem H Val i 7 a H H Ale 7 H Hg mam gimwl 0 quot Ber565 Arg590 forms polar interaction with uorophenyl substituent Guanidium is stacked over phenyl ring in Cop View m39 CnWHom Amide forms an additional hydrogen bonding interaction with Ser 565 unique to Lipitor and Crestor m 11 wdiml Arm5W HE n 7 mm o sulfonamide I Ber685 Notes Sulfonamide oxygen forms a h Oo nJiI interaction with Ser 565 L Sulfonamide also interacts uniquely with Arg 568 not shown Explains why rosuvastatin Crestor is most potent statin 39 Sulfone group important for HMGR binding as well as 6303 SQA e C 1 47 selective hepatocyte permeability via active transport proteins Patrick An Introduction to Medicinal Chemistry 5e Chapters 45 Introduction to CELL RECEPTORS l Structure and function of receptors NOTES Most cell receptors are integral protein complexes in the cell membrane Most bind either nascOWMMM h mm39g Hpiu n L W3 Si39e b 8x 1 Uriohms or ammW M13 39 4 4 n h The his comm mum receptors are found in the cytoplasm or the nucleus Most bind either steroid or thyroid hormones Each cell type has different receptor subtypes and concentrations making each cell type responsive to different chemical messengers 1 Structure and func on of receptors tin R GEp 1 Structure and function of receptors Chemical Messengers Ligands Neurotransmitters Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells such as muscle cells or another nervestually sheroL ltueci I g and responsible for messages between Thwarted can g HormonesGrowth Factors Chemicals released from specific cells or glands and which travel w Iona 5RSenas to bind with receptors on mg Q Srgaeai l1ng gt3 CLUS car m whole OQciV at Usually longlived H I Cytokines Small proteins released in higher concentrations during a 3H9 3 9mm 3 610 ch Gets a g esp immune cells Travel short distances to bind with receptors on e tow age can paracrine or the L95 that released the ligands autocrine 1 Structure and function of receptors Mechanism Occupancy Theory Change in receptor conformation induced t upon binding results in a domino effect known as Signal mam 0 g 9 inside the cell a A a b m concentration of chemical messenger to induce a dramatic change in concentration of ions or biomolecules Within the cell Chemical messenger usually does not enter the cell Ligand departs the receptor unchanged 61330 cich tofl CQnSJ nl39 a 0 0 e VQNI 7 V Z c L f a 11 R WL a J 7 f i 3amp3nd Ari Birgin Pod 6a axed cos an 5 C 566191514ng cr gmsS or 1 2 Overall Process of ReceptorMessenger Interaction Signal transduction Nam Binding interactions must be strong enough to hold the messenger suf ciently long for signal transduction to take place Interactions must be veak enough to allow the messenger to depart 0 Designing molecules with stronger binding interactions results in drugs that block the binding site nlakdan CS at inhlb ar so 1 3 Maj or Receptor Classes GATED ION CHANNEL IONOTROPICY MEMBRANE 39GPROTEIN COUPLED RECEPTORS BOUND 39KINASE LINKED RECEPTORS INTRACELLULAR NUCLEAR j quot reggae DNA Nam W les cn PHM HM Sk m RESPONSE TIME msecs seconds minutes hours to weeks 21 Ion Channel Receptors 11 General principles Gated ion channels are speci c for certain ions Na Ca2 Cl39 K and ligands typically speci c neurotransmitters Ions ow across cell membrane down concentration gradient Rapidly polarizes or depolarizes nerve membranes 22 LigandGated Ion Channel Receptors Binding Site many ligand gated ion channels have binding sites on a multiple subunits Receptor 9 Messenger A viii nial 1 u Cell membrane 39 Kquot Timembrane 39l 3 a a I f Iri We in W ion channel a opens Four or ve Integral gisrcoprotema W w WW 5 E m subumts comblnatlons of different QHACW 0 1 9 G subunits e xiigiiFi rd L Speci c cation channels for K Na Caquot Speci c anion channels for C139 Amino Terminal Domain Ligand Binding Domain MR Tm t mm 106 mm 4p 5 subunit TM protein GICR 90 rotated Bottom 55 Angstmms 23 LigandGated Ion Channel Receptors u 23 Ga nr F H Fast response measured in msec Binding of messenger leads direCtly to ion ow across cell membrane Ion ow secondary effect signal transduction 31 GProtein Coupled Receptors m ma Comm wwd PCC Q39W C2543 in cl o 5 SC 0sz Physiological Roles Vision taste smell quot khha slier oml mom re olgin on e g serotonin GABA glutamate dOpamine immune system regulation and in ammation 2 WWW MNOUS mm a a transmission e g blood pressure heart rate digestion cell density sensing homeostasis e g water balance body temperature growth and metastasis of some types of tumors GPCRs classi ed into six superfamilies based on protein sequence homology 800 different genes encode for 1000s of GPCRs 150 GPCRs orphm recng r5 have no known function GEM Ginmu M Fm W s 3mg Him quot no man QM Ha Tagm sign i frquot quot Hm i M i I L A We s II magma i 55mm V r mum V mustmu L is a j 39 394 V A39h I d A quot THEM ti V x n I39 HSNV if iwnmn 2 quot Wle 151m A i A man tiling 31 GProtein Coupled Receptors Receptor Types and Subtypes Receptor types and subtypes not equally distributed amongst tissues Chemical messengers for one subtype may not bind or not bind well to a Hg different subtype Heart muscle Adipose cells Bronchial muscle GI tract l H0 M Hz 51 adreneriic recEptors B3 adrener c receptors 0L1 amp B2 adrenergic receptors 0L1 12 amp B2 adrenergic receptors Dopamine A Monoamines pocket in TM helices B Peptide Hormones top of TM helices extracellular loops N terminal chain C NonPeptide Hormones extracellular loops N terminal chain D Glutamate N terminal chain zw onag l o I i nnmce ptor aim ylaw eye cAMP i Glycogen Protein kinase A Inhibitor inactive Catalytic E subunit of PKA In g39aibitarP Phosphatase Glycogen 39 ite sygnthaseP inactive Y Phosphorylase Phosphorylase kinase inactive kinaseP active Ifhosnhorylase b Phosphorylase a mactIve active Giycngen 4 Glnc asel pm5phate Prot in serves dual role r 66431 0 Dlus Eu m Receptor binds messenger peptide hormones growth tlactors cytokines leading to an induced fit Reaction then catalysed within cell Overexpression related to several cancers eg lung GI leukemias underexpession to developmental defects and hormone eg insulin resistance messenger 9 messenger V i A induced t A 1 active site in quot closed quot closed open intracellular reaction Extracellular Nterminal chain Hydrophilic transmembrane region cthelix Catalytic binding region1 K domain A closed in resting state Intracellular C terminal c 02H chain dries n4 pictsph l I itquot Lilla 5lt LT Ligand nding Cell membrane E v 1 l Inactive EGFR monomers 0 Binding site for EGF O EGF epidermal growth factor 0 Active site of tyrosine kinase r and dimerisa ner l l a r 912m l I quotquotoH m Induced t opens tyrosine kinase active sites each subunit catalyses phosphorylation of other 39 P0 0P ATP ADP P P Phosphorylated Tyr residues allow association of speci c signalling proteins or enzymes that initiate kinase cascades associated yvith activation of growth factors Section bivalent protein ligand 5439 wth and differentiation 5 WERE 5 A Diquot 114 h J g o 1 E b Gene transcription 5 395 F39 m r Raf inactive gt Raf active 1 Mek inactive Mek active Map kinase inactive gt Map kinase active 1 Transcription factor active Transcription factor inactive 9 than H dmc Hence Regulate ligands control which proteins are produced in a cell and are powerful targets for in uencing cellular function Often called nuclear r wggm d fmgn t Ligands must be filmy 3le I Binding leads to conformation changes that trigger protein association and DNA binding thereby regulating transcription 0 Response times are typically hours to days 3w WSS ic A meonmuea Ca eiPPCSS M U Se i J 39 39 Ok nal 39 are in 3prqu GeminiA IILHQ39 4Q no Structural Organization of Nuclear Receptors Ntenninal Hinge Ctenninal domain region domain DIM binding binding 39 39 omain DBD dmnan ELDEJ Also Pmds H coactlvator I and DNA BED r Crystal structure of progesterone receptor DBD dimer 1 The two zinc ngers contain Cys and His residues Allow SZn 0r NZn interactions androgen estrogen glucocorticoid and progesterone receptors Co activator protein Recepto r ligand Dim erisa on complex L 4 a A i 5 Complex binds to DNA 2 Binds to WI 6 Transcription switched on or off 3 Receptor 1 scio n recruitment of RM Ft pa N Mk 4 Binds 7 a 3 an H chn brmwm or blocking of the operator l forms a transcription factor 1 7 Protein synthesis activated or repressed Momme quot E o a quotJ r 5 Mn JIglompla a dasscio kaa W for coraprdssi retinoic acid retinoid X and thyroid hormone receptors I Craft 9quot quotI39 u r N 4quot 1WLhIpULlc nj nuclear Patrick An Introduction 9 to Medicinal Chemistry 5e m g y fthfm c l GETS PI v 39 39 ii 4 13quot a iv e f m 496quot 1 nomawalmlr in in 539 I Deac plim as mower am I 119 quotI K i a Pailsmats of Agonis39 11 lutroduc 3961st mimic the natural messenger of a receptor Agonists hind reversibly to the binding site and produce the same induced t as the natural messenger receptor is usually activated 0 Agonists are often similar in structure to Eugenw S WSW Agonist 39 39 Agnnist 7 I E Induced t 9 Signal transduction I of Example om hwotetieal i39 van der Waals binding region Binding groups 39 It 3955 in e Eiiriilliigt hiiu Neurotransmitter 1quot 7 0f E39Iample Ifa hypothetical it EieCHu gigHQ l gof aioq 39no 0Yl u hi W i f w n RDHUFE INDUCED Kay 7 4 Frr th mg mr Induced t allows stronger binding interactions Conformation eh age End39s m Ur l of Agn nisf Current binding groups Ionic blndlna H a rs 111mm Hb iljl l grillElla van dor Wuln bondng group Hypothetical neurotransmitter Possible agonists with similar binding groups Notes Identify important binding interactions in natural messenger Agonists are designed to have functional groups capable of same interactions 0 Usually require saw number cg inWHO j 3 legs 39xnmctbnsz a mist doecrsk oiad w iu 093 W 39tnkfcvchn339 Qynpjr b ahds i Qq Rae 14 Cu quot19 binding I quotL l glide Emma Structure I has one weak binding Structure 11 has 2 of the 3 required group negligible activity binding groups weak activity of L5 position of a Nu Interactlon Notes Binding groups must be positioned such that they can interact with complementary binding regions at the same time 39 Example has three binding groups but only two can bind simultaneously Example will have 90 b OCH Ekq a Enantiomens of a chiral molecule Th1 Quadioqu on has End 9 in as 5cong bi at as s mul 39 v oak Nata 0 One enantiomer of a chiral drug normally binds more effectively than the other 0 Different enantiomers likely to have EH5 in amcie b de s 39 l39 l Threewpoint Binding Hypothesis 11 Design of ngong chw 1 DH Hm gquot on 39n c g amp an mIlmrl r r Receptor c c39cjpccsr not occupied Eplmphrim 1m Ictive Eplnlphrlm more nctivc Nata i All chiral drugs whose enantiomers have different biological activities must have may not bm i o 1 nk i m i u lE WS39 with the receptor assuming they associate with same receptor L7 Ename Fill Agonists 5 16 hi d that makes Hn39is Enerimcpo m3 Acetylcholine Nicotine Epib atidine Endogenous Ligand of nAChRs Full Agonist of nAChRs Full Agonist of some nAChRs nAChRs nicotinic acetylcholine ligandgated ion channel receptors Create an action potential in CNS and PNS neurons when bound by ligand R Asmi s Cagx ole 0339 UPO Bind Dose Reapcnu 397 ECsoquot in who mew Edgon3 1 5 bod ED5Q gt in VND Shae iajonisg 35 unknowa 3 The an black Q ns maxim responsz 1617 or 30 3 1 P 0 Mphr 3 Srap id if s more pol cw quotIMWN HAL Que SFQ9N53 n yeen 39 5 L or 3935 3quot Cm I w 4 4r ECSO 5C EDS Caro Jets ResPQnSQ gm t Chang in ion uorescmm Countsmin bocyf 0 N1th talc YiSUo or True Ail rapeuse W VJe O M i m 2 6 05 7 57225 d 7 399 Qucm 1nd Res0 rue bio R6an 5 QRM SNen Q5 Design uf39Ago 18 and shape H I i Illa1 p Y I f E H H N we Nu Fit I39ll milling VEIIJII r Notes Agonist must have correct size and shape to t binding site Groups preventing access are called SWIG 6 Mail 8 5M6 Agents which enhance receptor activity by binding to an allosteric binding site rather than the messenger binding site Example Cinacalcet Sensipar Allosteric modulator for a Gprotein coupled receptor called the calciumsensing receptor makes more sensitive to Ca2 thereby limiting PTH release Used to treat thyroid problems associated with kidney failure and thyroid cancers Other common AChE inhibitors U liefquot 1quot a i l I I ll nk 39 3Nquot quot4 39 mgr Donepizil Aricept Emple HEEME 39 a i wuji lgwae l w 1 Weak antiM Galantam1neRazadyne s an a CD39S Treatment for early stage Alzheimer s and mlld to I g moderate vascular cognitive impairment Tacrine Cognex Competitive inhibitor of acetylcholinesterase AChE and allosteric modulator for nicotinic cholinergic receptors ligandgated ion channels which enhance ACh release by neurons Reversible Atagonisu Notes Antagonist binds reversibly to the binding site 0 Different or no induced fit means receptor 15 Level of antagoi ism depends on strength Inf antagonist E 03 1063 M lo hell Netti 7 Messenger is blocked from the binding site 0 Increasing the messenger concentration reverses antagonism If All Perfect fit antagonists bind to the binding site but fail to preduce the correct induced t receptor is not activated of Antago 39 Antagonists can form binding interactions with binding regions in the binding site not used by the natural messenger C Extra binding regions 1 A of Antagunim Antagonists can form binding interactions with extra binding regions neighboring the binding site of the natural messenger l Hbond binding region is lonlc blndln HHgMe I 9 I r l Hypothetical L neurotransmitter I oi Antagnnis Induced t resulting from binding of the normal messenger Induced fit ptagtm Different induced t resulting from extra binding interaction Initial binding Dian of an antagonist for the 39 Action of the 39f39den receptor Binding sixlc AFZ regions a 7 Keg yam t tipKIU Oestrogen Dimerisntion amp 39 receplor exposureof V transcription 0 W AFZ regions factor Transcription P t 8 W i a E323 puci cd FEW gceptor Design 39 an antagonist for the oestrogen 1 Binding interactions for oestradiol His 524 quotF in Glu3 3 e i luf310 J H 0 quot Hydrophobic skeleton 2 m LE3 Ll i m 3 r Oestradiol nil haw1quotquot H Giu AFQBQJ p Binding site is spacious and hydrophobic Nam Phenol group of oestradiol is positioned in narrow slot Orients rest of molecule 32 Design of an antagoist for the receptor Binding interactions for raloxifene WW awe nits 0 m SH UCIUPE Rnc m rooPS Cz m ulim 0S Iquot lair 7 F 39 pmgc bros h ch ick QHquot39As 3539 ae uil i m6 coiling 3 Side 1 7 His 524 cham 39 I39I 0 OH H quott In A6394 Raloxifene Raloxifene Evista is an antagonist postmenopausal osteoporosis and breast cancer chemopreventative Phenol groups mimic phenol and alcohol of oestradiol Interaction with Asp351 is important for antagonist activity Side chain prevents receptor helix H12 folding over as lid AF2 binding region not revealed so coactivator cannot bind Notes


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