Search and Structure Design of Physiologically Active Compounds

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AACIMP 2009 Summer School lecture by Victor Kuzmin. "Environmental Chemoinfornatics" course.

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Search and Structure Design of Physiologically Active Compounds

  1. 1. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 1 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c « , » . . , .
  2. 2. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 2 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c (1929 – 1983)
  3. 3. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 3 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Augusto Compte (1798-1857) in 1830: "…every attempt to employ mathematical methods in the study of chemical questions must be considered profoundly irrational and contrary to the spirit of chemistry. . ." Louis Joseph Gay-Lussac (1778-1850) in 1808: "We are perhaps not far removed from the time when we shall be able to submit the bulk of chemical phenomena to calculation"
  4. 4. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 4 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c George S. Hammond: - , .“ (Norris Award Lecture, 1968)
  5. 5. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 5 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Weininger : "There are 10180 possible drugs, 1018 likely drugs, 107 known compounds, 106 commercially available compounds, 106 compounds in corporate databases, 104 compounds in drug databases, 103 commercial drugs and 102 profitable drugs " J. Chem. Inf. Comput. Sci., 37, 138 (1997)
  6. 6. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 6 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c 25% 10% 50% 15% ~ 1000 .$ Ooms, F. Curr. Med. Chem. 2000, 7, 141-158 6
  7. 7. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 7 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c 45% - 28% - 11% - 5% - 2% - 14% - de novo HOOC COOH H3C N CH3
  8. 8. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 8 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c !) , , - ”c
  9. 9. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 9 re re he he k k lic lic High throughput screening C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c HTS robot Compound transfer robot “High throughput screening”- - , “ ”. - - . HTS , - , - . “ Facilities which normally only industry had can now increasingly be found as well at universities”
  10. 10. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 10 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c DOCKING OF CONSTRUCTED SELECTIVE ANTAGONIST OF mGluR1
  11. 11. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 11 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c LUDI, LeapFrog, LigBuilder Grow Link ) )
  12. 12. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 12 re re he he k k lic lic QSAR C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c (Quantitative Structure-Activity Relationship) QSAR , , . QSAR - , , ( ) . . .
  13. 13. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 13 re re he he k k lic lic QSAR C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c 1815 – W. Black: , . 1863 – A. Cros: , . 1894 – E. Fisher: « – ». 1913 – P. Ehrilich: , . 1962 – . Hansch: – . 1964 – S.M. Free, J.W. Wilson: . 1974 – B. Pullman, D. Pullman: . 1988 – R.D. Cramer, D.E. Patterson: CoMFA – 1989 – “The International QSAR Society” 2007 – “The Cheminformatics and QSAR Society” (945 ) QSAR Dorzolamide ( ), Saquinavir, Indinavir, Ritonavir, Nelfinavir ( ) Phospholipase A2 inhibitors ( )
  14. 14. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 14 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Quantitative Structure – Activity Relationship 1D 3H7O2N », «CODESSA», H O «HQSAR», «DRAGON» 2D H3C NH2 OH CoMFA, CoMSiA, HASL, 3D 4D
  15. 15. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 15 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c
  16. 16. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 16 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c
  17. 17. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 17 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c , . , HOMO, , LUMO, , . . , - _ N : C N , NN, HCCN, (2D- ) (3D- ), C CCCO, . 3D- 1D 2D 3D, 4D _ - _ 2D- 3D- ( ) ,
  18. 18. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 18 re re he he : k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c : [Randic, ; Kier-Hall, ], [W] , , , , , : , , ( ), , , , HOMO-LUMO- , , , , ) , , . , , .
  19. 19. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 19 re re he he k k Structure-Activity(Property) Relationships lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Additive schemes: A= Ai n (sum 1,2,. . . N) A = A0 + Ai n (sum 1,2,. . . N) Hammett eq.: pK = Hansch Approach (correlation of biological activity with lipophilicity, Hammett and Taft constants of substituents) : log(1/C) = k1 logP - k2 (logP)2 + k3 + k4 Es + k0 C. Hansch, T. Fujita J.Am.Chem.Soc. 1964, 86, 1616; C. Hansch Acc. Chem. Res. 1969, 2, 232. O Anticonvulsant activity of 1,4-benzodiazepinones: NH (R = Cl, Br, CN, NO2, CF3, N(CH3)2, SCH3, SEt, n-BuS, SOCH3) R N log(1/C) = 0.144 - 0.307 2 +1.291 + 4.558 Ph n=10, r=0.87, s=0.47 E.J.Lien, R.C.H.Liao, H.G.Shinouda J.Pharm.Sci. 1979, 68, 463.
  20. 20. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 20 Structure-Activity(Property) re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Relationships Fragmental and subsructural approach: Bioactivity(BA) = aA+bB+cC+. . . nN Free-Wilson method (additivity approach): Bioactivity(BA) = BA0+ BAip sip (sip = 1 or 0) X Antiadrenergic activity of substituted N,N-dimethyl-a-bromophenylamines: Y CHCH2N(CH3)2 Br Log(1/C) = -0.301 (m-F) + 0.207 (m-Cl) + 0.434(m-Br) + 0.579(m-I) + 0.454(m-CH3) +0.340(p-F) +0.768(p-Cl) + 1.02(p-Br) + 1.429(p-I) + 1.256(p-CH3) + 7.821 N = 22, r = 0.969, s = 0.194
  21. 21. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 21 re re he he k k lic lic C C w om «… w om w w w. w. A B B Y Y.c A B B Y Y.c «… , ». ». Hermann L., 1868. Brown A., 1868 ( ) ( )
  22. 22. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 22 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Randic Index ( ) CH3 C1 = ( i j)-1/2 bonds CH CH2 C2 C3 CH3 CH3 C5 C4 1 C1 C2 C3 C4 C5 1 3 3 2 C1 1 0 0 0 2 C2 1 1 0 1 4 1 1 C3 0 1 1 0 C4 0 0 1 0 C5 0 1 0 0 = 1/(3)1/2+1/(3)1/2+1/(6)1/2+1/(2)1/2=2.27
  23. 23. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 23 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Hologram QSAR
  24. 24. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 24 re re he he CoMFA k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c Comparative Molecular Field Analysis
  25. 25. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 25 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c
  26. 26. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 26 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c INFORMATIO (Latina) – ", " ". , . ” / . / .” / . / – .” / / , . ====================================================== » ; =n m m1 m2 m3 …. mk ; k n; mi mj = 0; mi = ni ; ni = n i : pi = ni/n : I=- pi log2 pi ============================================================ : MIN: M = m1 ; n = n1 ; p1 = 1 ; I = I` = 0 MAX: ni = 1 ; pi = 1/n ; I = log2 n ; I` = n log2 n
  27. 27. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c I 3 1 4 lb (1 4) 2 1 8 lb(1 8) 2,24 bit
  28. 28. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 28 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c ” . . . . I=0 I 0 ============================================================ , , . .
  29. 29. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 29 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c A B B Y Y.c . I(A) = lb(N/1), I(B) = lb(N/8), I(C) = lb(N/16), I(D) = lb(N/24) N– .
  30. 30. F T ra n sf o F T ra n sf o PD rm PD rm Y Y Y Y er er ABB ABB y y bu bu 2.0 2.0 to to 30 re re he he k k lic lic C C w om , w om w w w. w. A B B Y Y.c A B B Y Y.c .

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