Search and Structure Design of Physiologically Active Compounds
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Search and Structure Design of Physiologically Active Compounds

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

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

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    Search and Structure Design of Physiologically Active Compounds Search and Structure Design of Physiologically Active Compounds Presentation Transcript

    • 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 « , » . . , .
    • 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)
    • 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"
    • 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)
    • 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)
    • 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
    • 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
    • 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
    • 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”
    • 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
    • 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 ) )
    • 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 - , , ( ) . . .
    • 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 ( )
    • 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
    • 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
    • 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
    • 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- ( ) ,
    • 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- , , , , ) , , . , , .
    • 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.
    • 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
    • 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 ( ) ( )
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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 ============================================================ , , . .
    • 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– .
    • 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 .
    • 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 31 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 . Br F
    • 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 32 re re he he k k lic lic C C om QSAR om w w w w w. w. A B B Y Y.c A B B Y Y.c 1. . 2. , - . 3. . 4. QSAR- .
    • 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 33 re re he he k k lic lic C C om QSAR om w w w w w. w. A B B Y Y.c A B B Y Y.c . . . . . 1 2.2 QSAR 1 2.1 2.5 OH 2 3.0 A = f (S1,S2,S3,…,SM) 2 Cl 3.2 2.6 O O NH2 3 4.1 3 4.0 4.2 … … … …… … … O N 0.5 DA? . . . . 1 CH2 ? 2.6 2 NH ? 5.0 S1 S2 S3 … SM 3 ? 6.0 1.2 1. 1.7 … 1.9 HN NH 3 … … … … 2.7 2. 3.4 … 2.1 O 8 3.3 4. 0.1 … - 8 2.1 H C H C … … … … … … NH2 NH2 O ”, “ ” O O O 1 2 8 … 10 HN O NH2 NH2 O
    • 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 34 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
    • 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 35 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 m^ Ai = f [mxk(i)] , mx (i) - k i- , m- QSAR R2, Q2, R2test1 1 m^ - k- i- Ai m- QSAR i=1,N; m=1,M M ^ ^ Ai = m ^ Ai) M m=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 36 re re QSAR 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 (Domain Applicability – DA) DA T2 DA x x * * * * * * T1 * * x x x * T1, T2 R - - DA *- x DA R= d av + 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 37 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 4D 1.4; 2.3; 3.1 1; 2; 3; 4 3D +; - 2D - @; #; $; % 1D
    • 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 38 re re he he k k lic lic C C w om w om (SiRMS) w w w. w. A B B Y Y.c A B B Y Y.c : n!/4! /(n-4)!, n- •« » H • ………………….. Cl ( ) • ………………………………..
    • 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 39 re re he he k k lic lic C C w om w om w w w. w. A B B Y Y.c QSAR A B B Y Y.c CoMFA CODESSA HASL EMMA GRID DRAGON HQSAR CoMSiA O 3D H3C 2D OH 2D - 4D 2D O NH2 H3C OH 2D-4D NH2 3D 1 0 0 0 0 0 0 1 - , ., 1 0, 1 0 1 . . 0 0 0, 1 1 1- , 0-
    • 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 40 re re QSAR 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 Sutherland J.J.; O’Brien L.A.; Weaver D.F. A Angiotensin Converting Comparison of Methods for Modeling Quantitative Structure—Activity Relationships. Enzyme (ACE) inhibitors J. Med. Chem. 2004, 47, 5541-5554 R3 R4 R1 X CoMFA - Comparative Molecular Field Analysis Y N CoMSiA - Comparative Molecular Similarity Indices n N Analysis H EVA - Eigenvalue Analysis R2 O HQSAR - Holographic QSAR – 76 – 38 . Cerius2 - QSAR software 1 0.9 0.8 0.7 R22- R Q2 2- Q 0.6 R2test R 2 t- 0.5 0.4 0.3 0.2 CoMFA CoMSIA EVA HQSAR SiRMS(2D) SiRMS(3D)
    • 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 41 re re he he k k lic lic C C w om QSAR w om w w w. w. A B B Y Y.c A B B Y Y.c
    • 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 42 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 , % O N H2N H2N 40 40 28 H3C N CH3 O O H3C O N 15 14 8 O H3C HO N N N O H H O -4 -15 -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 43 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 5- E=2.1 kcal/mol, E=2.9 kcal/mol, lgTID50=1.1 lgTID50=0.6
    • 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 44 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 20% 30% electrostatic hydrophobic 5% H - bonding dispersionic 10% other individuality of 5% atoms 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 45 Combinational QSAR Modeling of Chemical 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 Toxicants Tested Against Tetrahymena Pyriformis Participants: UNC - University of North Carolina, Chapel Hill, NC, USA LPU - Louis Pasteur University, Strasbourg, France UI - University of Insubria, Varese, Italy UK - University of Kalmar, Kalmar, Sweden UBC - University of British Columbia,Vancouver, BC, Canada VCCLAB - German Research Center for Environmental Health, Munich, Germany PCI – A.V. Bogatsky Phys-Chem Institute NAS of Ukraine, Odessa, Ukraine 0.9 Training Set: 644 0.85 compounds; R2t1 Test Set 1: 339 compounds; 0.8 R2t2 Test Set 2: 110 compounds 0.75 UNC – Dragon, KNN; 0.7 LPU – CODESSA, MLR; UI – Dragon, OLS; 0.65 UK – Dragon, PLS; 0.6 UBC – IND, SVM; 0.55 VCCLAB – E-S+TI;ASSN PCI – SiRMS; PLS 0.5 UNC ULP UI UK VCCLAB UBC CONS PCI
    • 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 46 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 in vitro 1( ) N NH2 H2N NH2 N N O S O NH N N HO OH H3C CH3 HBB H3C OH HO N N O N HO N S S N HO O O N CH3 O N H3C NH2 PTU-23 S-7 O O N H3C O CH3 O O L. Nikolaeva, A. S. Galabov. O CH3 N In vitro inhibitory effects of O dual combinations of CH3 picornavirus replication inhibitors.// Acta virologica, 1999
    • 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 47 Developed Consensus QSAR Model 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 Observed vs predicted lgIC50 for external set Y = lgIC50 of Poliovirus 1 Mahoney replication, µmolar 3 8 – fold external cross validation 2,5 (every drug + all its mixtures out) 2 Work Set: 46 objects (8 drugs + 38 mixtures) 1,5 Models selected: 1 472 SiRMS 2D PLS models Antisynergism Observed Additivity R2 > 0.89; Consensus model: Synergism 0,5 Q2 > 0.86; R2 = 0.94; Single A<3 S (ws) = 0.25; 0 R2test = 0.80; -0,5 S (ts) = 0.45 -1 -1,5 -1,50 -1,00 -0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00 Predicted
    • 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 48 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 N O N N O N NH2 + NH2 N CH3 + O S O > O S O N H3C CH3 H3C CH3 N N NH2 + O N CH3 > + O N CH3 > N HO H3C N > O N N > N NH2 + > N S CH3 + N N O N N N > N + N O
    • 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 49 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 1:1 PTU-23 PTU-23 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 50 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
    • 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 51 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
    • 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 52 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 - - ............... . - - - - ………………………………….. - . ” HIGH TROUGHPUT SCREENING “HIT” “ LEAD”
    • 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 53 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 “This discipline concerns itself with the application of novel and nontrivial mathematics in a chemical context.” Dennis Rouvray, Edithor of J.Math.Chem. “ Mathematical Chemistry is a particular branch of theoretical chemistry with a great deal of emphasis on topology, graph theory, group theory, and related subject”. Löwdin P.-O. , - . , . , , .
    • 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 54 54 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 , , “high-throughput screening” » ( ), «De novo» , , .» QSAR « » , » « » ( ) ( )
    • 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 55 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 . , , , , , (“assembling”) , , " G. N. Lewis
    • 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 56 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 ( , - .) : Structure-based design , : de-novo design , : QSAR (Qualitative Structure-Activity Relationship) : “ high throughput screening”