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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

Valuable small compound

Plavix™, Tamiflu™, Lipitor™

1 plavix
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
blood coagulation
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
1 plavix1
1. Plavix ™의 작용

혈액 응고반응

what is plavix
What is plavix ?
  • Pro-drug인Clopidogrel은 간에서

cytochrome P450 효소에 의해 activation

가장 중요한 activation 특징;

Generation of sulfhydryl group

p2y 12 platelet membrane adp receptor
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
mechanism of plavix
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.
where is the point of disulfide bond
Where is the point of disulfide bond?
  • GPCR의 특징: extracellular loop domain이 ligand binding에 매우 중요
  • P2Y12 : loop domain의 cystein
2 lipitor
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
cholesterol biosynthesis
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
what if
What if?
  • HMG-CoAreductaseinhibition ?
  • Statin계열의 의약품; HMG-CoArecutase inhibitor
  • Atorvastatin(Lipitor™):

HMG-CoAreductase 의 competitive inhibitor로 작용cholesterol 합성 저해

mechanism of lipitor
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
how strong binding can be made
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)
slide26

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

in conclusion
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)

3 tamiflu
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
viral neuraminidase
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

slide34

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
mechanism of oseltamivir
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
slide39

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
slide41

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.
slide43
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