valuable small compound
DESCRIPTION
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?. - PowerPoint PPT PresentationTRANSCRIPT
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Valuable small compound
Plavix™, Tamiflu™, Lipi-tor™
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1. Plavix ™1. 뇌졸중 , 심근경색 또는 말초동맥성질환이 있는 환자에서 죽상동맥경화성 증상의 개선2. 급성관상동맥증후군 환자에서 죽상동맥경화성 증상 ( 심혈관계 이상으로 인한 사망 , 심근경색 , 뇌졸중 또는 불응성 허혈 ) 의 개선3. 혈전 생성 억제 작용 , blood clotting inhibi-
tior
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Blood coagulation? 1. 조직에 상처 발생시 조직에서 혈장으로
ADP(adenosine diphosphate) 유출 2. platelet( 혈소판 ) 표면 ADP receptor 인
P2Y12 에 ADP 결합 3. ADP receptor 의 ligand binding glyco-
protein complex pathway 4. Glycoprotein complex: fibrinogen, fi-
bronectin and von Willebrand factor 등의 binding receptor blood clotting final common pathway
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Aspirin mechanism
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1. Plavix ™ 의 작용혈액 응고반응
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Clopidogrel
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What is plavix ? Pro-drug 인 Clopidogrel 은 간에서 cytochrome P450 효소에 의해 activation
가장 중요한 activation 특징 ; Generation of sulfhydryl group
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Activation of plavix
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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
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Mechanism of plavix Key step; activation and irreversible binding activation of pro-drug sulfhydryl group 간에서 활성화 된 plavix 가 platelet recep-
tor 에 irreversible binding Irreversible biding = covalent bond =
disulfide bond 따라서 간에서의 활성화가 매우 중요하게 작용 .
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Where is the point of disulfide bond? GPCR 의 특징 : extracellular loop domain이 ligand binding 에 매우 중요 P2Y12 : loop domain 의 cystein
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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
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Cholesterol biosynthesis? Lipid metabolism 의 한 갈래 ( 간에서 진행 ) Acetyl-CoA 와 Acetoacetyl-CoA 로 부터
ring structure 의 molecule 합성 Key regulation site; HMG-CoA reduc-
tase HMG-CoA reductase: HMG-CoA 를
mevalonate 로 reduction 하는 enzyme, rate-limiting step enzyme
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What if? HMG-CoA reductase inhibition ? Statin 계열의 의약품 ; HMG-CoA recutase
inhibitor Atorvastatin(Lipitor™): HMG-CoA reductase 의 competitive in-
hibitor 로 작용 cholesterol 합성 저해
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Atorvastatin
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Mechanism of Lipitor HMG-CoA reductase (
http://www.uniprot.org/uniprot/P04035);
Transmembrane protein(ER, Peroxi-some)
Competitive inhibition: substrate 와 in-hibitor 간의 구조적 유사성에 기인 , HMG-like moiety
Bulky hydrophobic group??? Ki=0.1~2.3nM, Km=4μM ; inhibitor 의 강한 결합력
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HMG-CoA reductase 의 active site: tetramer 의 각 monomer 간의 interface로 이루어져 있다 .
CoA binding α-helix(c-terminal): con-formation change inhibitor 의 bulky hydrophobic group 이 active site 에 들어갈 수 있게 한다 . (enzyme flexibility이용 )
How strong binding can be made?
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Weak interaction 의 기여 ; 1. HMG-like moiety 와 enzyme 의 polar
interaction(H-bonding, ionic pair): en-zyme cis-loop 과 HMG-like moiety 는 많은 polar interaction 을 이룸 shape and charge comple-mentarity 형성
2. Bulky hydrophobic group 과 enzyme active pocket 의 non-polar interaction: enzyme pocket 내부의 hydrophobic amino acid와 inhibitor 의 hydrophobic group 이 van der waals interaction 형성 surface complementar-ity
3. 그 외의 weak interaction: carbonyl oxygen on the ring, fluorophenyl group과 enzyme polar amino acid 간의 interaction
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In conclusion A number of van der waals interaction
between bulky hydrophobic ring struc-ture and enzyme active pocket is im-portant for strong binding of Lipitor to HMG-CoA reductase
To make van der waals interaction, en-zyme flexibility is necessary
(ex; La11 helix)
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3. Tamiflu™ 1 세 이상의 인플루엔자 A 또는 B 바이러스 감염증 치료 및 예방 Competitive inhibitor of Influenza virus
neuraminidase oseltamivir (tamiflu™) Viral neuraminidase structure 에 기반한
drug design 으로 개발된 inhibitor
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oseltamivir
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Viral neuraminidase Glycosidase substrate: sialic acid (neuraminic acid)Glycoprotein 의 glycan chain 의 sialic acid Exo&Endo- neuraminidase viral neu-
raminidase 는 non-reducing end 의 sialic acid 를 특이적으로 잘라냄 exo-glycosi-dase
9 종류의 subtype 두 그룹으로 분류 ; 1. N1,N4,N5,N8 2. N2,N3,N6,N7,N9
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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
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Active site
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Mechanism of oseltamivir Influenza virus 의 envelop protein:
hemagglutinin, neuraminidase Host 로부터 exit 하기 위해 neu-
raminidase activity 가 요구됨 oseltamivir : neuraminidase 의 competi-
tive inhibitor 로 작용 virion exit 불가감염확산 방지
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Active site; adjascent 150-cavity & 150-loop
3 Arg(118, 292, 371), Glu276; polar in-teraction with sialic acid
많은 polar amino acid 가 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
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Open conformation: low energy state Closed conformation: high energy state Openclosed conformation change:
protein-ligand interaction 증가 ( 강한 결합 ) Conformation change 의 변화가 더 강한
drug design 에 응용될 가능성이 높다 .
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종합 및 결론 Drug 의 target; GPCR or specific en-
zyme inhibition (reversible or irre-versible)
Drug design 의 필수 과제 ; target macro molecule 의 physiological structure
Protein flexibility