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Valuable small compound

Valuable small compound. Plavix ™ , Tamiflu ™ , Lipitor ™. 1. Plavix ™. 뇌졸중 , 심근경색 또는 말초동맥성질환이 있는 환자에서 죽상동맥경화성 증상의 개선 급성관상동맥증후군 환자에서 죽상동맥경화성 증상 ( 심혈관계 이상으로 인한 사망 , 심근경색 , 뇌졸중 또는 불응성 허혈 ) 의 개선 혈전 생성 억제 작용 , blood clotting inhibitior. Blood coagulation?.

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Valuable small compound

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  1. Valuable small compound Plavix™, Tamiflu™, Lipitor™

  2. 1. Plavix ™ • 뇌졸중, 심근경색 또는 말초동맥성질환이 있는 환자에서 죽상동맥경화성 증상의 개선 • 급성관상동맥증후군 환자에서 죽상동맥경화성 증상(심혈관계 이상으로 인한 사망, 심근경색, 뇌졸중 또는 불응성허혈)의 개선 • 혈전 생성 억제 작용, blood clotting inhibitior

  3. Blood coagulation? • 1. 조직에 상처 발생시 조직에서 혈장으로 ADP(adenosine diphosphate) 유출 • 2. platelet(혈소판)표면 ADP receptor인 P2Y12에 ADP 결합 • 3. ADP receptor 의 ligand binding glycoprotein complex pathway • 4. Glycoprotein complex: fibrinogen, fibronectin and von Willebrand factor 등의 binding receptor  blood clotting final common pathway

  4. Aspirin mechanism

  5. 1. Plavix ™의 작용 혈액 응고반응

  6. Clopidogrel

  7. What is plavix ? • Pro-drug인Clopidogrel은 간에서 cytochrome P450 효소에 의해 activation 가장 중요한 activation 특징; Generation of sulfhydryl group

  8. Activation of plavix

  9. P2Y12 (platelet membrane ADP receptor) • G-protein coupled receptor • Location: Platelet membrane surface • Function: ADP receptor  key site for blood coagulation • http://www.uniprot.org/uniprot/Q9H244

  10. Mechanism of plavix • Key step; activation and irreversible binding • activation of pro-drug sulfhydryl group • 간에서 활성화 된 plavix가 platelet receptor에 irreversible binding • Irreversible biding = covalent bond = disulfide bond • 따라서 간에서의 활성화가 매우 중요하게 작용.

  11. Where is the point of disulfide bond? • GPCR의 특징: extracellular loop domain이 ligand binding에 매우 중요 • P2Y12 : loop domain의 cystein

  12. 2. Lipitor™ • 1. 지질 대사 이상 증후군 환자의 증상완화, 유전적, 비유전적 이상지질혈증(고지혈증)의 증상 완화 • 2. 심혈관계 질환의 예방 • 3. lowering blood cholesterol level

  13. Cholesterol biosynthesis? • Lipid metabolism의 한 갈래(간에서 진행) • Acetyl-CoA와 Acetoacetyl-CoA로 부터ring structure의 molecule 합성 • Key regulation site; HMG-CoAreductase • HMG-CoAreductase: HMG-CoA를 mevalonate로 reduction하는 enzyme, rate-limiting step enzyme

  14. What if? • HMG-CoAreductaseinhibition ? • Statin계열의 의약품; HMG-CoArecutase inhibitor • Atorvastatin(Lipitor™): HMG-CoAreductase 의 competitive inhibitor로 작용cholesterol 합성 저해

  15. Atorvastatin

  16. Mechanism of Lipitor • HMG-CoAreductase (http://www.uniprot.org/uniprot/P04035); • Transmembrane protein(ER, Peroxisome) • Competitive inhibition: substrate와 inhibitor 간의 구조적 유사성에 기인, HMG-like moiety • Bulky hydrophobic group??? • Ki=0.1~2.3nM, Km=4μM ; inhibitor의 강한 결합력

  17. How strong binding can be made? • HMG-CoAreductase의 active site: tetramer의 각 monomer 간의 interface로 이루어져 있다. • CoAbinding α-helix(c-terminal): conformation change  inhibitor의 bulky hydrophobic group이 active site에 들어갈 수 있게 한다. (enzyme flexibility이용)

  18. Weak interaction의 기여; • 1. HMG-like moiety와 enzyme의 polar interaction(H-bonding, ionic pair): enzyme cis-loop과 HMG-like moiety는 많은 polar interaction을 이룸shape and charge complementarity형성 • 2. Bulky hydrophobic group과 enzyme active pocket의 non-polar interaction: enzyme pocket 내부의 hydrophobic amino acid와 inhibitor의 hydrophobic group이 van derwaals interaction형성surface complementarity • 3. 그 외의 weak interaction: carbonyl oxygen on the ring, fluorophenyl group과 enzyme polar amino acid 간의 interaction

  19. In conclusion • A number of van derwaals interaction between bulky hydrophobic ring structure and enzyme active pocket is important for strong binding of Lipitor to HMG-CoAreductase • To make van derwaals interaction, enzyme flexibility is necessary (ex; La11 helix)

  20. 3. Tamiflu™ • 1세 이상의 인플루엔자 A 또는 B 바이러스 감염증 치료 및 예방 • Competitive inhibitor of Influenza virus neuraminidase  oseltamivir (tamiflu™) • Viral neuraminidase structure에 기반한 drug design으로 개발된 inhibitor

  21. oseltamivir

  22. Viral neuraminidase • Glycosidase • substrate: sialic acid (neuraminic acid) Glycoprotein의 glycan chain의 sialic acid • Exo&Endo- neuraminidase  viral neuraminidase는 non-reducing end의 sialic acid를 특이적으로 잘라냄exo-glycosidase • 9종류의 subtype • 두 그룹으로 분류; 1. N1,N4,N5,N8 2. N2,N3,N6,N7,N9

  23. Group1, Group2 의 active site 구조 차이 antiviral drug(ex;tamiflu) resistance • Tetramer consist of 4 identical monomer • Very well conserved overall structure among different subtypes

  24. Active site

  25. Mechanism of oseltamivir • Influenza virus의 envelop protein: hemagglutinin, neuraminidase • Host로부터 exit 하기 위해 neuraminidase activity가 요구됨 • oseltamivir : neuraminidase의competitive inhibitor 로 작용virion exit 불가감염확산 방지

  26. Active site; adjascent 150-cavity & 150-loop • 3 Arg(118, 292, 371), Glu276; polar interaction with sialic acid • 많은 polar amino acid가 다른 subtype간에 conservation  substrate binding • Oseltamivir binding conformation change of 150-Loop conformation change of 150-cavity & cavity volume change(closed conformation)more stronger binding of inhibitor

  27. Open conformation: low energy state • Closed conformation: high energy state • Openclosed conformation change: protein-ligand interaction 증가(강한 결합) • Conformation change의 변화가 더 강한 drugdesign에 응용될 가능성이 높다.

  28. 종합 및 결론 • Drug의 target; GPCR or specific enzyme inhibition (reversible or irreversible) • Drug design 의 필수 과제; target macro molecule의 physiological structure • Protein flexibility

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