FORCES THAT DETERMINE LIGAND-RECEPTOR INTERACTIONS
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1 Corpora non agunt nisi fixata Paul Ehrlich Address in Pathology on Chemotherapeutics: Scientific Principles, Methods, and Results Lancet II, 445 (1913) FRCES TAT DETERMIE LIGAD-RECEPTR ITERACTIS Favourable forces electrostatic interactions hydrogen bonds hydrophobic effect van der Waals interactions desolvation of receptor and ligand Unfavourable forces loss of translational and rotational entropy loss of internal rotations in ligand (entropic) loss of solvation energy of receptor and ligand (enthalpic) conformational changes in receptor P. G. Strange TiPS 17, 38 (1996) Strychnine C 3 Morphine 3 C 3 C C C + C 3 d-tubocurarine Codeine icotine C 3 C 3 C 3
2 !! ρ σ π Analysis, A Method for the Correlation of Biological Activity and Chemical Structure C. ansch & T. Fujita J. Am. Chem. Soc. 86, 1616 (1964) A Mathematical Contribution to Structure-Activity Studies S. M. Free, Jr. & J. W. Wilson J. Med. Chem. 7, 395 (1964) Physiological activity Φ = f (C) (own & Fraser, 1868) Φ = f ( C) Biological activity = f (a i X i, m) Linear Free Energy Relationships B.a. = µ + Σ a ij X ij de novo model (X ij = 1, 0) µ = overall mean of b.a. values (Free & Wilson, 1964) µ = b.a. of unsubstituted parent molecule (Fujita & Ban, 1971) Biological activity = log (1/C) = k 1 (X ) + k (X E ) + k 3 (X S ) + ε parametric model (ansch & Fujita, 1964)! " # $ " # " % # &! & ' ( ) & " # * σ " # $% & & ' & ( ' ) * ) +++ & & ) π ", $-,./ & 3'1 # & &
3 ID Block Block description Desc. o. 1 constitutional descriptors 48 topological descriptors walk and path counts 47 4 connectivity indices 33 5 information indices 47 6 D autocorrelations 96 7 edge adjacency indices BCUT descriptors 64 9 topological charge indices 1 10 eigenvalue-based indices Randic molecular profiles 41 1 geometrical descriptors RDF descriptors D-MoRSE descriptors WIM descriptors GETAWAY descriptors functional group counts atom-centred fragments charge descriptors 14 0 molecular properties 9 +, - 6,. / $.0 6 Log P A = Log [A] 1-octanol [A] water 6 $ 1 *, $ 3 *0, 7 π C 3 = logp - logp C 3 /, / "#$%&&&' ("% '
4
5 ''& & '& ' ) + ''& & '& ' ) + 3& 9 / / '' : 3 ' 9 ;7 ' 9 ' 9 R ESS TSS RSS RSS = 1 TSS TSS TSS TSS = ( y i y ) i= 1 ESS = ( y calc y i= 1 i= 1, i ) RSS = ( y i y calc ), i "A QSAR Investigation of Dihydrofolate Reductase Inhibition by Baker Triazines Based Upon Molecular Shape Analysis" A. J. opfinger J. Am. Chem. Soc. 10, 7196 (1980) "Molecular Graphics and QSAR in the Study of Enzyme-Ligand Interactions. n the Definition of Bioreceptors" C. ansch & T. E. Klein Acc. Chem. Res. 19, 39 (1986) "Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins" R. D. Cramer, III, D. E. Patterson & J. D. Bunce J. Am. Chem. Soc. 110, 5959 (1988) "Prediction of Drug Binding Affinities by Comparative Binding Energy Analysis" A. R. rtiz, M. T. Pisabarro, F. Gago & R. Wade J. Med. Chem. 38, 681 (1995)
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9 / "< B$ &,/,. 8 3)R L 8L. /,., 9 Principal Component Analysis ) B "++& 5 & & '& & )$5 & & & '& & 9 Partial Least Squares & 5 & & 0 & & ) ''& 5 & & '& ) & '' + / B,.,' riginal Table Compounds excluded Groups of crossvalidation Derivation of a model Prediction of excluded compounds $ " 4 " 4 Predictive Residual Sum of Squares (PRESS) Differences ';, = i= 1 SDEP = 1 (Yexp(i) Ypred(i)) / / ''/ B4 Q (Yexp(i) Ypred(i)) (Yexp(i) Yexp ) PRESS =
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11 ;% ; ;3?/ ( / (,.;S ( 3?( % +. ). ; = ; (; +.) ). ; : R!+Q T9 : R!+C A ;, R!+I ;, 7 R+!Q : R!+C C T9 : R!+C E ;, R!+IE ;, 7 R+:< ( " 4! 9 R<: : RI C. Pérez, M. Pastor, A. R. rtiz & F. Gago J. Med. Chem. 41, 836 (1998). ", *- *). / $*% " " 4
12 ( ;..?%,- ; ;?% ;;% 3 3 ; ;% ; L /./.3?( % %,3?3?( %?% 3?S,;3;3;% 3 ( ;. ;?4 3?( % ( ;.4.? 3?( % ) "$ B ),;?/ 3?( % $ ".$ 7 $ '".$ 7 R;. K ";. U; $ R n i=1 wu $ ) ".$ sel i i + B B B ' ", % 1 $' $ C %* * 3 & % %$, + ( + ( $$* " $) " : R!+Q A T9 : R!+C! ;, R!+C : ;, 7 R!+Q < R<: : RI C. Pérez, M. Pastor, A. R. rtiz & F. Gago J. Med. Chem. 41, 836 (1998) : R!+A!T9 : R!+C < ;, R!+IA ;, 7 R!+E A / ( 8?% ; n i=1 wu sel i i + C
13 : R!+A T9 : R!+Q ;, R!+II R@Q
14 -0 & ' 4 $*( 1, *%& *( *%( +, & J! Selected energy contributions in the best CMBIE model J. Kmuní εk, S. Luengo, F. Gago, A.R. rtiz, R.C. Wade & J. Damborsk Biochemistry, 40, (001) training set prediction set Phe17Trp mutant enzyme Trp175Tyr mutant enzyme new substrate + Phe17Trp mutant enzyme Modulation of Binding Strength in Active Site Inhibitors of Acetylcholinesterase Studied by Comparative Binding Energy (CMBIE) Analysis I C & X C & 9 * & 9 * Martín-Santamaría, S.; Muñoz-Muriedas, J.; Luque, F.J.; Gago, F. J. Med. Chem. 47, (004)
15 P ) ) / B '& / ( 8?% ; : R!+C I ;,R!+C Q R<E % *,. ''" P $ % *,. ''"$
16 , ) M'& / ( 8?% ; ;,R!+A < Chemometrical Identification of Mutations in IV-1 Reverse Transcriptase Conferring Resistance or Enhanced Sensitivity to Arylsulfonylbenzonitriles : R!+A E T9 : R!+Q A T ;,R!+@!"<,/ $ R:E M A BB:<@B& * B8!:I"A $ :C Q B:C A ":!!@$ : R!+A E A 9 : R!+Q E "R:C T@,/ $ 4!I R'' Apo enzyme Inhibited enzyme 5 ; 6 : ;< < / = = > : ;< ; ;6 < 5 ; ; % B ) L Q / R5 '' Targeted molecular dynamics E = 0.5 k r (rmsd trmsd)
17 & )'& 0.!<-?4 B & & 3 '& B5 & BB9 "$' & & & ' "'R!+E 0 B D B: $ Apo K103 enzyme Inhibited K103 enzyme '5 B3 '#!<% 3 '& * B8+T += & )'& 0.!<-?4 B & & >!:I"@C $ E <Q IBE <Q C =? _50ps B C D@ "µ$ ' -?4 B3 ''% % 3? % / 8!+<A ±!+!Q E!+:E ±!+!Q E 5 ; 6 (! C +!±!+:Q ( B < 3!+Q E ±!+!Q E Q +E ±!+E C " $ " $ : ;< < 0 : ;< < 5 ; 6 ( : ;< ;0 : ;< ;5 ; 6 ( 0.5_750ps _1ns ; ; "# / B@@:$ 3& )7 " / BC Q $,;33" # B!C I$ 7 " P Q IC $ / " $ ;' * ; "3/ B:E $!+!E A ±!+!!+!<I±!+!@!+!!:±!+!!!+!C ±!+!!Q!+!!E ±!+!!!+!!@±!+!!:!+!:A ±!+!@ :+±!+:!+Q <±!+I:!+!!C ±!+!!!E!+@<±!+!<E!+!!@±!+!!!+@±!+!I@!+!<:±!+!E ,!+!<C ±!+!!:!+!I±!+!!< 50 50,"'$ E +@±!+@A :+E E!V & ) 9 & ))-?4 B3) E!V + 3 " $/ W"$ T ) ) X < -Y 3, " $ " $ 8* +":!!@$
18 5 ; 6 =@ % ETRAVIRIE : ;< < 4, 80, 8 8 4, C3 14 rmsd (Å) 3C ( ; 6 : ;< < #!<% -?4 B 3) 0) ; 6 ( 4 5 B -?4 B 3) 0) time (ps) =@ * B8 -?4 K? & ) Z, J+T + =3& ) ' & ) )! :C ":!$ C E C!BC E C Q & '' / ADP? & ) )[ Sorbitol + ADP Sorbitol dehydrogenase AD + AD Fructose R, 1 R R R3 - R1=R3=, R= 3 R1=C3, R=, R3=,& ::. <!! C S 3C CF3 3& S / CF3 Tolrestat :A Q < 3 Zopolrestat C B % 1 8 C Cl!< > '% 1 ' &. & Aldose reductase Glucose +T 8 * F F Zenarestat Sorbinil %,U de la Fuente, J.A.; Manzanaro, S.; G. de Quesada, T.; Reymundo, I.; Luengo, S.M.; Gago, F. J. Med. Chem. 46: (003)
19 , )Z;.) IC 50 = 6.4 ± 1.1 µm Estado A G 1 λ G λ G -1 3 λ -1 G 1 λ G λ G -1 3 λ -1 G 1 λ G λ G -1 3 λ -1 Estado B ' =;& >, )Z;.) =9 / > (λ 1 ) (λ ) IC 50 = 5% Σ G i (ruta 1) = Σ G i (ruta ) = Σ G i (ruta 3) G(λ) = k T ln (λ) G BA + G AB = 0
20 / G 1 R A + L R A L R + L G 1 RL 1 1 G 3 G G G 4 3 G 4 G R B + L R B L R + L RL halr:adp G binding (1) IC 50 = 6.4 ± 1.1 µm halr:adp + :1 G = G G 1 = G 4 G 3.) ' Z 9 )' )) ) + ' [ & 7 Z ± ± ± ± 0.5 G 3 G kcal mol -1 E C ;D@ kcal mol -1 ± D6 kcal B mol -1 kcal 4 mol -1 halr:adp + + G binding () halr:adp + : IC 50 = 5% de la Fuente et al. J. Med. Chem. 46(4): (003) % F C0 T -1 C8 Asn7 Glu356 G +1 Arg364 Asp533 ;+T.P +T3 / +T. 7 +T?5 +T?& )& +T8 / +T + = '? ) 5 & & B & >"" "$ <C A IB<Q!C
21 " 3?E C?)$ c a 3 C R1 b d 3 C R1 C 3,; % 3,( 4 ( ;B federico.gago@uah.es
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