Chapter 4. ???????(SAR)

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Chapter 4. ???????(SAR)
Structure-Activity Relationships

• ????
• ???????(Targets)
• II. ????
• III. ??-????????????
• IV. ??????

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I. ???????(Targets)
??(Receptors)?????????????,??????????
?????????(signal transduction pathway) ?(Enzymes)
????(Ion Channels) ???? ??(Nucleic
Acids) ????(Immune System) ??(Gene)
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??(Receptors)

• ????????????????????????????
• ????????
• ??????????????????
• ??????????
• ?????(isomers)
• ????????,?
• ???(Agonist),???????,?????,?????????
• ???(antagonist),???????,?????,??????????
• ????(?3-1)
• ???????????????,???????????
• GPCR (G protein coupled receptor)
• ??-?????
• ???????

????
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1. Direct ligand-gated ion channel receptor
   ????,45???a??(2025 AA)??????????,???????,???????
   ?????,??????????????????,GABAA??,?????,5-?????,???
   ??

Acetylcholine
g-aminobutyric acid (GABA)
5-hydroxy tryptamine (5-HT)
glutamic acid
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2YMD Choline receptor/5-HT
4MS3 GABAb receptor/GABA (Nature 2013)
4OO9 glutamate receptor 5 (Nature 2014)
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????(Ion channels)
Ca2, K, Na, Cl-??
4MS2 Ca2 channel (Nature 2014)
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2. GPCR (?????4060 ) G-Protein heterotrimer
(a/b/g), ??GTP GPCR ????,N???,7?a helix(2025 AA
each) ??????,?????? ??GPCR???????,?????,????,????
??,??,???? ?????????Ca2, K?? ?3-2,
3-3 ???GPCR???b-?????????H1?????H2?????m???5-HT3
??????D2?? (?3-2)
4NC3 5-HT2B (Science 2014)
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3.Tyrosine protein kinase receptor
?????????????,?????tyrosine residue, ??insuline,
cytokine, EGFR,PDGFR,VEGFR,Bcr-abl
kinase ????,400700AA,??????????,??????,????ATP???
?,ATP??????tyrosine???????????(oncogene)??????,???
???????(?3-3)
Imatinib (Glivec by Novartis for 10 cancers eg.
CML, GISTs ), targeting Bcr-Abl kinase
Leflonomide for RA, psoriatic arthritis,
targeting PDGFR, F80 t1/22 weeks
4. Nuclear hormone receptor ??DNA??,??????(??????
??????????)?????????D3????A????(?3-4)
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?(Enzymes)
???????????/?????????? ??????????????????????????
??,1/3 ???????? ?????????????????Isozyme????,?????
??,?????????????????,??off-target???
Omeprezole targeting H/K ATPase, Reversible
inhibitor
Methotrexate targeting DHFR for cancer, abortion
etc. 1000X vs folate, almost irreversible
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????

• ???????????????5-HT?????????????????P-???
• ??DNA, RNA
• ????
• ???????????????????????????????????????????????
• ????????????????
• ???????
• ??????
• ????????????????????????,????,??????????????

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II. ????

• ????????(????)
• ???????(?????)
• ???????????
• ????????
• ????????,?????????

???(specificity) ?????(????,????),??(???),??(????)
???????????gt30100,?????????????????30X?? ???????
???????,?????????????,????????
Isoproterenol ??????
Adrenaline ???
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?????????

• General structure elucidation procedure
• Determine molecular formula by MS
• Degree of Unsaturation 2 (2 x Carbons)
  Nitrogens - Hydrogens - Halogens/2
• Acquire 1H, HSQC and HMBC, write down chemical
  shifts and build connectivity
• Acquire 1D TOCSY NOESY to resolve ambiguity
• Draw a tentative structure and check consistency
  with spectra
• Note the presence of peaks can be proof of
  nuclear and its connectivity
• the absence of peaks can NOT be proof of
  no connectivity!

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2nI1 Rule I1/2 for 1H, 19F, 13C and 15N
I1 for 2H n number of vicinal protons

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General rule the closer to N (O), the bigger
(even bigger) chemical shifts
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Karplus-Conroy Eq. 3JHH a cos2f - 0.28 (a
10 if flt90 a15 if f gt90) Martin Karplus 2013
Nobel laureate. (CHARMM, ??????????????????)
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Average JCH is around 146 Hz, as is normally used
in 13C-1H HSQC
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HMBC
Heteronuclear Multiple Bond Correlation Normally
detect 2J or 3J (ca. 3Hz) Do not confuse with
HMQC (heteronuclear multiple quantum
correlation, similar to HSQC)
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HMBC without 1J suppression
For small molecule, the splitted 1J correlation
can be intuitive to identify HSQC peaks Less s/n
compared with HSQC May need to adjust the long
range J coupling
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1H-1H Correlation
Through Bond
COSY 3J 1H-1H (Correlation Spectroscopy)
TOCSY Connectivity (Total Correlation
Spectroscopy) more useful)
Through Space NOESY(Nuclear Overhauser Effect
Spectroscopy) ROESY(Rotating frame Overhauser
Effect Spectroscopy) Detect spatial
correlation up to 5?
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Typical TOCSY
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Selection of NOESY and ROESY
600 1200
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NOESY Spectrum
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????
??????NMR???? ???????408?? ????? ???
???????????? 6-7?,??1?, ?? ??????????, ??
???????
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III. ??-????????????
????(Molecular recognition) ?????????????????????
(???????,??) ??????(?4-4)????,????,???? Ion-ion
interactionE?1/r, ????,-5-10kcal/mol ion-dipole
interaction E ?1/r2,-1-7kcal/mol Dipole-dipole
interaction E ?1/r3, -1-7kcal/mol Hydrogen-bond
-1-7kcal/mol N-HO??2.83.2A ???N-HOC??,
N-HO?150180o COH?100180o hydrogen bond
donor hydrogen bond acceptor Chelation
????/?????,?????????????????(????????)
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?????????????????????????????,???(RO5)
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???(pharmacophore)
Ehrlich????,?????????????????????????????,????????
???? ??????????????,?????????(????????????) ??????
???????,??????
Feature ????,?????,?????,?????,????,???? ????????
????(???????) ????????(gt10)????????(???,?????)???
??,?????????????????(HTS,FBDD??????)??????????
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????????????????????,????????????????
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????(privileged structure)
????
??steroide
????benzepine
??????pyridine

• ???????
• features, gt3 and lt6
• gt1 rings
• lt2 COOH
• Normal features-NH2,-CONH2,-OH, -CO, -SO2-,
  -SO2NH2, -COOH, HCONH2-, -COO-

?amidine
?carbamidine
?carbamide
??pyrrole
??indole
??thiazole
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???????

• ??/????-SO3H, -PO3H2, -COOH?????,???????
  ??????,?,?,????
• ????????/????????
• ?????,??,???,????,???????/?????
• ??F????????????CF3???Cl??,?????Cl????????????????
  ???????Cl/Br???????,?????????????I???
• ????????,??????????????,????????????
• ??/??????????????,??michael addition?????????
• ??/????????
• ????,?????????????,pKa, ?????,???,t1/2?

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????

• ????????,?????????????,?????
• ????
• ??
• ??

???,?????
E-????
Z-????
?E????
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????
???????????????????????? Conformation
Preferential / Pharmacophoric ??????????????? ????
????????????????
?? ????,??????
???
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??????????????
?????????90o
?????????180o
??b-B ????
??a ??????? C-C-N????? ????
??b-A
??b ????? C-C-N??? ????
????????????????
??b-B ?????? ???
??b-A ?????? ???
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????

1. ????????????,?b-????,???,????,????,a,b-????/?,???
   ??,????????,????????/??/????????,??????,???????
2. ??????????(?5-2)????????(?????????????,???)??????
   ???(??hERG?????,????)

Retinoic acid, ????????/???,???????
Astermizole, ???????,?????hERG K ion channel,
1999??
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????
???????????? ???????408?? ?????, 3-4?
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IV. ??????

• Quantitative Structure-Activity Relationships
  (QSAR)
• ?????????????????,???????????????????
• 2D QSAR (1960s) ???????3D???????,????????????
• Hansch-????(????????)
• Free-Wilson(??????????????????)
• Kier(?????)
• 3D QSAR (1988s) ????????????????,????????????????
  ???(?????????)
• Hopfinger ??????
• Crippen distance geometry
• Cramer Comparative molecular field analysis,
  CoMFA

??????????
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Hansch-????
Hammett???????????
IC50, EC50, LD50
Tafts steric constant
???????

1. ????????,????????????
2. ??????????in vivo /in vitro
3. ????????????/?????
4. ?????Hansch-????
5. ??????,????????,?????????????

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???????????????????