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BcKy;ҩ=ba! t`a![M" aºB kxf@3  a0B!̀f0;sawb+f* a0B!̀f@3  a0ڙ<7]!*2*EmWx70>!/ 1Vj!ПJjަwhw{,X}H7ZEP0$rwHC*bl&i[E#zn`$ߜ" F !R BF]FQ{Pkш:Yz0/JG tC=Jc,M w Hyoùf9r8$# ~y A1#!\ 붐M8C IT!15jԕ2熐Fڟ^5v@ P Fn3W'IENDB`M(  L )rEquation Equation.30,Microsoft Equation 3.0sEquation Equation.30,Microsoft Equation 3.0H/ 0|DTimes New Romanttsx: 0DVerdanaw Romanttsx: 0" DArialaw Romanttsx: 00DSymbolw Romanttsx: 0@DCourier Newmanttsx: 01 C .  @n?" dd@  @@`` $$0 OJ  ( 6.7%)6  )  %#"     )  "  !    (                      &1:D>phs?"-(./H&D$        5    ,*&:#$c+    D# (#'609 <o02  9"7G55H#;  &  (# F (0 '9  8  # # (   (0   0  6 s           !" #$ %&'*+,-./0145678 9\ ]^ _bcdeijklmno pqrwxy z{|~C'0  (b$^?^Y0*Y>ob$x#}?KRb$״d` ~$ks4)b$/W'YVh|n # 8b$x!\^TZ*Eb$|\w=ѧt4b$R-"҅N3Vb$zD _(x0Ҡ䈲 5 b$y3]^>Ӵs3ϩ-b$U3v_ !@WCb$Vqr_݊ `b$5nd.dt^nb$  2Covalent inhibition of protein kinases: Case study33X%PRELIMINARIES: ASSESSMENT OF RAW DATA,& 3Reproducibility: Fixed vs. optimized concentrations,43 LOutliers  Anomalous reaction progress,'&(Optimal maximum inhibitor concentrations,)(xInhibitor vs. enzyme concentration:  Tight Binding  Part 1,=<xInhibitor vs. enzyme concentration:  Tight Binding  Part 2,=<d,Substrate-only control: Linear or nonlinear?,-,Y7Assessment of data: Implications for method of analysis,87\9MATHEMATICAL MODELS: ALGEBRAIC VS. DIFFERENTIAL EQUATIONSP: ] Traditional method to analyze covalent inhibition data: Step 1,A:t Traditional method to analyze covalent inhibition data: Step 2,A:^p Traditional method: Underlying theoretical assumptions,98_;Alternate method: Differential equations (DynaFit software)L<* v|Differential equation method: Example  Afatinib: Data & model,?2 (wxDifferential equation method: Example  Afatinib: Parameters,=2 ( | Differential equation method: Example  Afatinib: Reproducibility,B2(8Final results: Biochemical activity vs. Cellular potency,9(P:CHECK UNDERLYING ASSUMPTIONS: BIMOLECULAR ASSOCIATION RATE,; xDifferential equation method: Example  Afatinib: Parameters==( <Varying assumed values of the association rate constant, kaIP=2 98Effect of assumed association rate constant: ConclusionsL9 'N1CHECK UNDERLYING ASSUMPTIONS: SUBSTRATE MECHANISM,2FSubstrate mechanism   Hit and Run L$ LSubstrate mechanism  Michaelis-Menten,'DSubstrate mechanism  Bi-Substrate,#  lSubstrate mechanism   Bi-Substrate : DynaFit notation,76 lSubstrate mechanism   Bi-Substrate : DynaFit notation,76/Presumed substrate mechanisms vs. kinact and Kit0",":Substrate mechanism  SummaryHSxTHE NEXT FRONTIER: MICROSCOPIC  ON AND  OFF RATE CONSTANTSN='xConfidence intervals for  on /  off rate constants: Method>='zConfidence intervals for  on /  off rate constants: Results>>(*hCellular potency vs. upper limit of  residence time H5 ThLower limit for the  on rate constant vs. kinact/Kix5++ +Summary and conclusions,,Acknowledgments/(C %-D.E/F0G1H3J4K5L6M7O8P9QJcKdOfQgViWjZk[l`mapbqcresutzv{w}xz{|}~   0` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>> <4(    6Lߒ P  T Click to edit Master title style! !  0   RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0 ``  X*  0 `   l*(    0 `   `* H  0޽h ? ̙33 Default Design0 0 P@(  4 4 Ne y y .   x*a00aa 4 N$v y y 3 .  z*a00aad 4 c $ ?  4 4 Nx y y 9 f  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S 4 T y y r   x*a00aa 4 T<~ y y r3   z*a00aaH 4 0ηo~ ? ̙3380___PPT10.pU(X p\x(  \ \ N,*_ ]e]e    _  p* AAA \ N-_ ]e]e %   _  r* AAA  \ T8_ ]e]e   _  p* AAA \ TB_ ]e]e %  _  r* AAAH \ 0ηo~ ? ̙3380___PPT10.CP) 0 0(  X  0A?`m  6x0  9 Covalent Inhibition Kinetics Application to EGFR KinaseL:3333XB  0D  $  <(3@W t  >Petr Kuzmi , Ph.D. BioKin, Ltd.^      XB  0D0H  0޽h ? ̙33y___PPT10Y+D=' _ = @B +  0   0 5t  (  t x t c $``   XB t 0D`X t 0A?`m )t <ԧ/t <ENZYME +t <  q1Epidermal Growth Factor Receptor (EGFR) Kinase $2.l  , 5t  ,,$D  0 *t  Bt ,t t9 COVALENT KINASE INHIBITORS<Q ,t  <d x 3Gilotrif (afatinib) Dacomitinib Neratinib ... ...P4  6  ll @ 2  4t  @2 ,$D  04 .t  <Hp 2 TLD___PPT9&  dtDetermine basic biochemical characteristics of inhibitors: initial binding affinity: Ki chemical reactivity: kinact<9<,V @` /t  B@ d  :GOALl l P 1t l P,$D  0 -t  0"` P PSchwartz, P.; Kuzmic, P. et al. (2014) Proc. Natl. Acad. Sci. USA. 111, 173-178.Q  9 0t  <l }@ ? REFERENCE H t 0޽h ? ̙33___PPT10+v㞌Dh' = @B D#' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*5t %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*5t D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*5t Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*4t %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*4t D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*4t Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*1t %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*1t D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*1t + k 0 p(  x  c $@ `   XB  0D`X  0A?`mH  0޽h ? ̙33y___PPT10Y+D=' _ = @B + % 0 \T  (   x  c $``   XB  0D`X  0A?`mV  C .Asheet-002 `z P@    P@ ,$D 0t   6|"`P ZB   s *D8c @ :  <L 0R ,$  0 : Both of these inhibitor concentrations cannot be correct.D;   <  06x,$  0 F Or can they ... ?1  <T$p0 D,$  0 A We will treat inhibitor concentrations as adjustable parameters.4B'E  <' IGLOBAL FIT OF COMBINED TRACES REQUIRES THAT CONCENTRATIONS ARE CONSISTENTtJ  3 3 3) 3  33H  0޽h ? ̙33f^___PPT10>+2xDz' 5= @B D5' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* ++0+ 0 ++0+ 0 ++0+ 0 +o  F 0 WO  (   x  c $``   XB  0D`X  0A?`mV  C .Asheet-0020@ z `     H 0` ,$D  0t2   6Ԕ"` 0@    <`   Y#Exclude this curve before analysis.$$6  << LABOUT 2% (10 / 400) OF KINETIC TRACES IN THIS DATA STE ARE CLEARLY ANOMALOUSbM 3  30 3  33H  0޽h ? ̙33___PPT10+DD|' = @B D7' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* +  G 0 @ 2(   x  c $إ``   XB  0D`X  0A?`mN  <Чl p8@,$  0 D Maximum concentrations are based on preliminary experiments (IC50).NE%   <P  .IDENTICAL MAXIMUM CONCENTRATION WOULD NOT WORK@/  3 33f  0A?"`  L H  0޽h ? ̙33___PPT10+PD' = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+ 0 +Z& H 0   `  ? (   x  c $|``   XB  0D`X  0A?`mf  0A?"`0? r  <K m@,$  0 j  Tight binding is not a property of the inhibitors.L6 P  <$pT 0,$  0 b  Tight binding has to do with assay conditions.22   <xaT !,$  0 `  TB means that [E]0 @ Ki or even [E]0 > Ki J1 ,   <p D ,$ 0 j [E]0 = 20 nMB    <D C ,$ 0 #Is [E]0 is very much lower than Ki?$   6o"` P,$D 0  63fo"`pP ,$D 0H  0޽h ? ̙33SK___PPT10++TD' = @B D' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* ++0+ 0 ++0+ 0 ++0+ 0 ++0+ 0 ++0+ 0 +1  0  y(  h  C 2Aconcplot-lin"` x  c $ ``    XB  0D`X  0A?`mz y    8 y ,$D 0ZB  s *D8cy% %   < @   T[Enzyme] = 20 nM( l   6V"`x a   <  r,$  0 U Inhibitor and enzyme concentrations are comparable. Inhibitor depletion does occur.PV5 H  0޽h ? ̙33___PPT10+Dt'  = @B D/' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+ 0 + s 0 m e   (   x   c $< ``    XB   0D`X   0A?`m^   C 6Asubdata-mark20  ` )   <   :,$  0 IGuess how much the slope (i.e., rate) changes between marked time points?$JEN   <%  @,$  0 DReaction rate changes by almost 50% from start to finish: NONLINEAR.NE  ,z  ``     `` ,$D  0&N  ``     `` f   C 6Asubdata-rate20 `` ZB   s *D> t   6jJ"`  z        ,$D 0`B   0D 0 0 `B   0D0    </ F0 :  ZDt"   <4 ,  @DF"x   <9 L + ,$ 0 rate DF/Dt  H   0޽h ? ̙33___PPT10+eD' E = @B D' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* ++0+ 0 ++0+ 0 ++0+ 0 + l 0 ~ v   (  x  c $xQ ``    XB  0D`X  0A?`m4  <S   @ Some curves will need to be excluded, preferably automatically.lA    <(] \ 0,$ 0  Concentrations will need to be treated as  unknown parameters.PAr  <d p,$ 0 f Inhibition depletion does occur ( tight binding ).P4 b  <l  ,$ 0 : Substrate depletion does occur (nonlinear control curve).l;   l  Pg   P9 ,$D 0t   63fjJ"` P0    <u  g  v@These facts will determine the choice of the mathematical model.AAfH  0޽h ? ̙33  ___PPT10 +¦`vD ' _ = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* ++0+0 ++0+0 ++0+0 + m 0 p(  x  c $P     XB  0D`X  0A?`mH  0޽h ? ̙33y___PPT10Y+D=' _ = @B +  p 0 LDp (  x  c $ ``    XB  0D`X  0A?`mS  < @~ Copeland, R. (2013) Evaluation of Enzyme Inhibitors in Drug Discovery Second Edition, J. Wiley, New York, Chapter 9 (sect. 9.1)L1% X  0A?Tp ^   64l v   0r ,$D 0x   S A ??#" `?  @   < v  $Determine kobs as a function of [I]0j%  t2   6>"` t2   6>"` G  <p F=x ;Reaction progress at a given inhibitor concentration, [I]0:D<6H  0޽h ? ̙335-___PPT10 +RD' _ = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*+O t 0 vn  0(  0x 0 c $ ``    XB 0 0D`X 0 0A?`mS 0 << @~ Copeland, R. (2013) Evaluation of Enzyme Inhibitors in Drug Discovery Second Edition, J. Wiley, New York, Chapter 9 (sect. 9.1)L1% ^ 0 6f 0 0A?"`@1 f2 0 0"`0 P ^ 0 6p 0 S A  ??#" `?p   f2 0 0"`  0 <H  r  97Nonlinear fit of kobs values to determine kinact and Ki8>H 0 0޽h ? ̙33y___PPT10Y+D=' _ = @B + q 0  w   (   x   c $x``  x XB   0D`X   0A?`m   <PD<4___PPT9 4Linearity of control curve Control progress curve ([I]0 = 0) must be strictly linear over time. No tight binding The noncovalent Ki value must be very much higher than [enzyme].   6 j/ @`   <(P B$ ,$ 0 }I Both of these assumptions are violated for the inhibitors in our series.JJR   <8x -t ,$ 0 J In fact, assumption #1 above is violated for all assays where [S]0 << KM.LKB  $l    < @,$D  0F   <@x x We cannot use the  traditional method of kinetic analysis.>= /ZB   s *DjJ  H   0޽h ? ̙33  ___PPT10 +{`|D ' = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +p+0+ 0 ++0+ 0 + r 0 ^ V  (  x  c $ ``    XB  0D`X  0A?`m  <, ~ dKuzmic, P. (2009)  DynaFit  A software package for enzymology Meth. Enzymol. 467, 247-280^\@ ,@l  \  \,$D 0  < jJ"` \ &v[mechanism] E + S ---> E + P : ksub E + I <==> E.I : kaI kdI E.I ---> E-I : kinactwwt(   <  A INPUT TEXT: l 00  @,$D 0   <p   \&INTERNALLY DERIVED MATHEMATICAL MODEL:''`   0A ?@2 00l `` p ` `p,$D  0`   0`` p   <  P   Csystem of differential equations solved by using numerical methodsBD H  0޽h ? ̙338 0 ___PPT10 +D ' = @B D ' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*+  v 0 `@>(  @x @ c $8 ``    XB @ 0D`X @ 0A?`m @ <  bDYNAFIT-GENERATED OUTPUT. 33x @ C BA *data-model-t001-g001"` < @ <$ Dv p global fit combined progress curves analyzed togetherD9  ", @ <  4a,$  0 Beechem, J. M. (1992) "Global analysis of biochemical and biophysical data Meth. Enzymol. 210, 37-54.fg& 6EH @ 0޽h ? ̙33___PPT10+˽D'   = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*@%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*@D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*@+8+0+@0 +0 w 0   H. (  Hx H c $ ``    XB H 0D`X H 0A?`m H <   bDYNAFIT-GENERATED OUTPUT. 33f H 0A ?"`b  H <8& \ 0 ,$ 0 Ki = kdI / kaIZ   6  H 6A >?"`@  ,$D 0  H <t0 | RP ,$ 0 -kaI = 10 M-1s-1 ... assumed (fixed constant).   +el z0 Hz0,$D 0t H 68c"`Pp 0t  H 68c"`p 0ZB H s *D8c ` p`B H 0D8c `p `' H <=  z Ki = 0.0314 / 10 = 0.00314 M`   Dl  p" H p",$D  0ZB H s *D| p  H <F  B  LFINAL RESULTS: Afatinib  Replicate 1:''J H <?  " "Ki = 3.14 nM kinact = 0.00204 s-1l#     $ H H 0޽h ? ̙33:2___PPT10+V!F#D' V = @B DA' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* H%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* H%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* H%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*H%(Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*H%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*HD' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*H+p+0+ H0 ++0+ H0 + x 0 &Py(  Px P c $`a ``    XB P 0D`X P 0A?`m P <0c P  ^(Replicate #1 Replicate #2 Replicate #3)) P <dh   VEACH  REPLICATE REPRESENT A SEPARATE PLATE@, 3 RB P s *D8cpLB P c $DPP  P <o  ~  kinact s-1J  LB P c $D  P <t * [ ~ Ki nMJ LB P c $D v P <T| ZI~ kinact / Ki M-1 s-1  $ LB P c $Dpp LB P c $DPpLB P c $D p LB P c $D   P <l D ,$ 0 J0.0020 0.0021 0.0025 !P <@ DK ,$ 0 A 3.1 3.1 4.0 "P <ܑ D ,$ 0 E10.4 10.5 9.9&l J`   &P` J ,$D  0`B #P 0D|p` ` B $P Bd J   @Reproducibility (n=3) of rate constants 5-15% for all compounds.lA H P 0޽h ? ̙33PH___PPT10(+8Dd'  = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* P%(D' =-o6Bdissolve*<3<* PD' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*!P%(D' =-o6Bdissolve*<3<*!PD' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*"P%(D' =-o6Bdissolve*<3<*"PDn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*&P%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*&PD' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*&P++0+ P0 ++0+!P0 ++0+"P0 + ~ 0 ` (  x  c $x``    XB  0D`X  0A?`mb  C ,Acell-ic50"`( w  < "`P `,$D 0 Ki: slope = +0.90 g  < "` :d ,$D 0 kinact: slope = -0.15n   < ,$  0 G... initial binding  <\  wd ,$  0 K... chemical reactivitym  <d @.,$  0 SCellular potency correlates strongly with binding, but only weakly with reactivity.^T#H  0޽h ? ̙33___PPT10+iD'  = @B D:' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*++0+0 ++0+0 ++0+0 ++0+0 ++0+0 + g 0 @p(  x  c $ `    XB  0D`X  0A?`mH  0޽h ? ̙33y___PPT10Y+D=' _ = @B + z 0 0 (  `(  ` `  H  ?"```    ^B ` 6D?`l ` 6A??"``m ` B ?"` bDYNAFIT-GENERATED OUTPUT. Z ` B4 ?"`\ 6  Ki = kdI / kaIr6r ` <A >??"`@    ` B ?"`| XV  -kaI = 10 M-1s-1 ... assumed (fixed constant).+ ` B GHj "``@ yrecall: we assumed this value@ ~ ` <#   ,$  0 xCould the final result be skewed by making an arbitrary assumption about the magnitude of the association rate constant?Jy.  6H ` 0޽h ?` ̙33___PPT10+MdD' ( = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*`%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*`D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*`+8+0+`0 +`) P 0 `](  x  c $x: ``    XB  0D`X  0A?`mr  <A >??"` ?  <2 >  kaI, M-1s-1d    LB  c $D`P LB  c $D pp    <G `Zd =ASSUMED   <E  *T  > 10 20 40    < C   !EXAMPLE: Afatinib, Replicate #1/3$"  l ` `,$D  0   <8A P `W4 JDETERMINED FROM DATA   <xW  W  kdI, s-1J    <^     kinact, s-1J  TB  c $Dp  <c   Ki, nMJ F  <j  kinact/Ki, M-1s-1      <$t  N ,$ 0 H0.0016 0.0016 0.0016  <Xy   ,$ 0 I0.037 0.074 0.148  <|  [  ,$ 0 ? 3.7 3.7 3.7  <x  V ' ,$  0 Ki = kdI / kaI6  <T   ,$ 0 B23.1 23.1 23.1H  0޽h ? ̙33;3___PPT10+*uD'  = @B D' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*++0+0 ++0+0 ++0+0 ++0+0 ++0+0 + Q 0     (  x  c $ ``    XB  0D`X  0A?`m  << "` nThe assumed value of the  on rate constant does effect the best-fit value of the dissociation ( off ) rate constant, kdI. The fitted value of kdI increases proportionally with the assumed value of kaI. Therefore the best-fit value of the inhibition constant, Ki, remains invariant. The inactivation rate constant, kinact, remains unaffected.*.2-"     = % by4=7l      ,$D  0ZB  s *D|    < d   >Assumptions about the  on rate constant have no effect on the best-fit values of kinact, Ki, and kinact/Ki.n. >S    < < ,$  0 However, the dissociation ( off ) rate constant remains undefined by this type of data.DX H  0޽h ? ̙33{ s ___PPT10S +;D '  = @B D ' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+ 0 + f 0  p(  x  c $ `    XB  0D`X  0A?`mH  0޽h ? ̙33y___PPT10Y+D=' _ = @B +V J 0 }u  (   x  c $ ``    XB  0D`X  0A?`m-  <  EASSUMING THAT THE MICHAELIS COMPLEX CONCENTRATION IS EFFECTIVELY ZERO`F 3 3 3 33h  c 2AegfrHR"`` 5  <4 3f"`T `0  v Justified by assuming that [S]0 << KM In our experiments KM e" 220 M and [S]0 = 13 M The model was used in Schwartz et al. 2014 (PNAS) @ H  0޽h ? ̙33y___PPT10Y+D=' _ = @B + K 0  t(   x  c $4 ``  4  XB  0D`X  0A?`m  <4  <ASSUMING THAT ATP COMPETITION CAN BE EXPRESSED THROUGH  APPARENT KivE 3 3 3  3 33Bh  c 2AegfrMM"`m   <4 3f"` E  b  S is the peptide substrate All inhibitors are ATP-competitive Therefore they are  S -noncompetitiverk  H  0޽h ? ̙33y___PPT10Y+D=' _ = @B + L 0  (   x  c $t&4 ``  4  XB  0D`X  0A?`mh  c 2AegfrBS"``p  <(4 3f"` `  4 Catalytic mechanism is  Bi Bi ordered ATP binds first, then peptide substrate  I is competitive with respect to ATP  I is (purely) noncompetitive w.r.t.  S Substrates are under  rapid equilibrium T 1H  0޽h ? ̙33y___PPT10Y+D=' _ = @B += { 0 h (  hx h c $84 ``  4  XB h 0D`X h 0A?`mn h 68:4 "`D,$  0 :[mechanism] E + ATP <==> E.ATP : kaT kdT*; .> h <|@4 p D DDYNAFIT INPUT:f  h 0A?"` |  h 0A?"`" ,$D 0_  h BE4 +,$  0 - S + E.ATP <==> S.E.ATP : kaS kdS..P LB  h c $Dp   h 0A?"`P e,$D 0 h <DM4 Z0h @ MECHANISM: * h BlQ4 m-,$  0 $S.E.ATP ---> P + E + ADP : kcat%%$ h 0A?"`W ,$D 0 h BV4  R ,$  0 t*E + I <==> E.I : kaI kdI+++ h 0A?"`  ,$D  0, h B[4  Fp ,$   0 &E.I ---> E-I : kinact''$ h <d`4 D P,$   0 e3Similarly for the remaining steps in the mechanism.44H h 0޽h ? ̙33/|/___PPT10\/+_* D-' n4 = @B D-' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hDn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* h%(D' =+4 8?dCB0-#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* hD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* h%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* hDn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* h%(D' =+4 8?dCB0-#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* hD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hDn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB0-#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hDn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB0-#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*hD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*h%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*hD' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*h+P+0+h0 ++0+ h0 ++0+h0 ++0+h0 ++0+h0 ++0+h0 +  | 0 kc  p(  px p c $l4 ``  4  XB p 0D`X p 0A?`m p <d4 @P} KDYNAFIT INPUT WINDOW:f p 0A?"``@l p 6jJ"` l [``  p`[` ,$D 0n p 0A?"`p`` t p 6"`[ {t p 6"`  H p 0޽h ? ̙335-___PPT10 +D' _ = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*p%(D' =-o6Bdissolve*<3<*p+% M 0  (   x  c $(4 ``  4  XB  0D`X  0A?`m   <44   !EXAMPLE: AFATINIB, REPLICATE #1/3@"  3 33 f  0A?"` 4  <04    kaI, M-1s-1d      <d4 $ 9FIXEDLB  c $D@0@  <h4   kdI, s-1J    <4  m  kinact, s-1J    <IJ4 vA  ^*Hit-and-Run Michaelis-Menten Bisubstrate++LB  c $D0`   < 4 K ,$ 0 U 10 10 160* 5  <4  Q ,$  0 [ATP]/KM,ATP = 16F LB  c $D` 0`   <4 v ,$ 0 G0.031 0.033 0.032  <l4  K ,$ 0 J0.0019 0.0019 0.0019l h`   h` ,$D  0TB   c $D0`    <4  Ki, nMJ    BL4  kdI/kaIF  )   <4 h  3.1 3.1 0.19 = 3.1/16   H  0޽h ? ̙33 ___PPT10+߰*D' 4 = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* ++0+ 0 ++0+ 0 ++0+ 0 ++0+ 0 +  O 0   @ P (   x  c $ 4 ``  4  XB  0D`X  0A?`m  < P D<4___PPT9 Basic characteristic of inhibitors (Ki, kinact) are essentially independent on the presumed substrate mechanism. The inactivation rate constant (kinact) is entirely invariant across all three substrate mechanisms. The initial binding affinity (Ki) needs to be corrected for ATP competition in the case of  Hit and Run and  Michaelis-Menten mechanisms: - Hit-and-Run or Michaelis-Menten: Divide the measured Kiapp value by [ATP]/KM,ATP to obtain true Ki - Bisubstrate: True Ki is obtained directly.V$   G F P    $d^ @`H  0޽h ? ̙33y___PPT10Y+D=' _ = @B + j 0 p(  x  c $h;     XB  0D`X  0A?`mH  0޽h ? ̙33y___PPT10Y+D=' _ = @B +D d 0 q i   (  x  c $2 ``    XB  0D`X  0A?`m   B* >"`0PtB  We cannot measure  on and  off rate constants as such. But can can estimate at least the lower limits of their confidence intervals.P1&  DC  0P J,$  0 nMETHOD:  Likelihood profile a.k.a.  Profile-t method8  l     ,$D  0  6<  D<4___PPT9 Watts, D.G. (1994) "Parameter estimates from nonlinear models Methods in Enzymology, vol. 240, pp. 23-36 Bates, D. M., and Watts, D. G. (1988) Nonlinear Regression Analysis and its Applications John Wiley, New York sec. 6.1 (pp. 200-216) - two biochemical examples ? (3H @`  6d    = REFERENCES: H  0޽h ? ̙33{ s ___PPT10S +{֋D ' e = @B D ' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* +8+0+0 + } 0 @ xT(  xx x c $^ ``    XB x 0D`X x 0A?`md  x <8w "`,$D 0 kon: slope = -0.88n e  x < "`P p$ ,$D 0 koff: slope = ~0.05n  x < p`,$  0 t... association rateD   x <, @  ,$  0 i... dissociation rate8 l x < p!0D,$  0 RCell IC50 correlates strongly with association rates. Dissociation has no impact.^Sb x C ,Acell-ic50"`@( H x 0޽h ? ̙33___PPT10+D'  = @B D:' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* x%(D' =-o6Bdissolve*<3<* xD' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* x%(D' =-o6Bdissolve*<3<* xD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* x%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<* xD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<* xD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*x%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*xD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*xD{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*x%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*xD' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*x++0+ x0 ++0+ x0 ++0+ x0 ++0+x0 ++0+x0 + c 0    K (  x  c $| ``    XB  0D`X  0A?`m  < @,$ 0 0 Lower limit for  off rate constant defines the upper limit for residence time.tQP  << ~P;  Z Drug-receptor residence time : t = 1 / koffL.!)  < @,$ 0 H Both minimum koff and maximum t is invariant across our compound panel.lI  7  < \ @,$  0 : This is unexpected in light of the  residence time theory of drug potency: Copeland, Pompliano & Meek (2006) Nature Rev. Drug Disc. 5, 730 Tummino & Copeland (2008) Biochemistry 47, 5481. Copeland (2011) Future Med. Chem. 3, 1491[$"  ,X -T'   <t ,E~ ,$ 0 9 However cellular IC50 varies by 3-4 orders of magnitude.2: $H  0޽h ? ̙33  ___PPT10` +>o{Dd '  = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*++0+0 ++0+0 ++0+0 ++0+ 0 +  i 0 rj(  x  c $ ``    XB  0D`X  0A?`md  C .Akon-approx"`(X   <D ,,$  0 ~kinact/Ki from rapid-equilibrium model is a good  proxy for minimal kon.J($ <H  0޽h ? ̙33___PPT10+PD'  = @B DD' = @BA?%,( < +O%,( < +D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*+8+0+0 + D 0    I (   x  c $ ``    XB  0D`X  0A?`m  0  D<4___PPT9 EQUILIBRIUM BINDING AFFINITY: Initial (non-covalent) binding seems more important for cell potency than chemical reactivity. BINDING DYNAMICS: Association rates seem more important for cell potency than dissociation rates (i.e.,  residence time ). kinact / Ki (rapid-equilibrium) appears to be a good proxy for the lower limit of the  on rate constant. i B _  b,b @`,l b `   b`,$D  0N   <| b ` &This work could not have been done using the  usual data-analysis method: - substrate depletion ([S]0 << KM) - inhibitor depletion ([I]0 ~ [E]0) S    ZB   s *D|  l     ,$D 0   <% "`  /use DynaFit to analyze covalent inhibition data40%n   033"` H  0޽h ? ̙33___PPT10+aDg' = @B D"' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<* D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<* D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* + E 0 " (   x  c $2 ``    XB  0D`X  0A?`m  < 4  0  . 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R4}RTy\M}=/|^7n6WF=[/ xVJ@=3S*" \F+QA7hB|4VSm ?؍7­wI D܈=&ɹ3sz-ty5BgcJzf?7CO?XMiyV-iy#o[l}1!)+v N? p柏8<9>(vLj_NEI_ջPZNİv1ajm:cc35D?6DH^qÅ÷ G[_fLUv!"f#VɑQl~EZ$KE4-/o!^T<)0$y}rg/U`~bK->YVڱVW6i1_7:Hr MVK]>bC"g$ Pۅ&t{@.!(Q/$}0 t' *X(+#-C/c13p3579<#>C@J cBDN@mFHS LVJM #OCQl"-%e:OcSUWY[r`Cs"u2^cqz@#`CbGcdwf85h$sjYlo#qv1Oh+'0T hp  Algebraic Model..507Microsoft PowerPoint@Pzv@E1(@s}*@3-mGSg  )'    """)))UUUMMMBBB999|PP3f333f3333f3ffffff3f̙3ff333f333333333f33333333f33f3ff3f3f3f3333f33̙33333f333333f3333f3ffffff3f33ff3f3f3f3fff3ffffffffff3ffff̙fff3fffff3fff333f3f3ff3ff33f̙̙3̙ff̙̙̙3f̙3f333f3333f3ffffff3f̙3f3f3f333f3333f3ffffff3f̙3f3ffffffffff!___wwwup4'A x(xKʦ """)))UUUMMMBBB999|PP3f3333f333ff3fffff3f3f̙f3333f3333333333f3333333f3f33ff3f3f3f3333f3333333f3̙33333f333ff3ffffff3f33f3ff3f3f3ffff3fffffffff3fffffff3f̙ffff3ff333f3ff33fff33f3ff̙3f3f3333f333ff3fffff̙̙3̙f̙̙̙3f̙3f3f3333f333ff3fffff3f3f̙3ffffffffff!___www¼rrIrrrrrnnrr%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%՜.+,0$     On-screen Show.T)&& -Times New RomanVerdanaArialSymbol Courier NewDefault DesignMicrosoft Equation 3.0Slide 13Covalent inhibition of protein kinases: Case study&PRELIMINARIES: ASSESSMENT OF RAW DATA4Reproducibility: Fixed vs. optimized concentrations'Outliers Anomalous reaction progress)Optimal maximum inhibitor concentrations=Inhibitor vs. enzyme concentration: Tight Binding Part 1=Inhibitor vs. enzyme concentration: Tight Binding Part 2-Substrate-only control: Linear or nonlinear?8Assessment of data: Implications for method of analysis:MATHEMATICAL MODELS: ALGEBRAIC VS. DIFFERENTIAL EQUATIONSATraditional method to analyze covalent inhibition data: Step 1ATraditional method to analyze covalent inhibition data: Step 29Traditional method: Underlying theoretical assumptions<Alternate method: Differential equations (DynaFit software)?Differential equation method: Example Afatinib: Data & model=Differential equation method: Example Afatinib: ParametersBDifferential equation method: Example Afatinib: Reproducibility9Final results: Biochemical activity vs. Cellular potency;CHECK UNDERLYING ASSUMPTIONS: BIMOLECULAR ASSOCIATION RATE=Differential equation method: Example Afatinib: Parameters=Varying assumed values of the association rate constant, kaI9Effect of assumed association rate constant: Conclusions2CHECK UNDERLYING ASSUMPTIONS: SUBSTRATE MECHANISM$Substrate mechanism Hit and Run'Substrate mechanism Michaelis-Menten#Substrate mechanism Bi-Substrate7Substrate mechanism Bi-Substrate: DynaFit notation7Substrate mechanism Bi-Substrate: DynaFit notation0Presumed substrate mechanisms vs. kinact and KiSubstrate mechanism Summary=THE NEXT FRONTIER: MICROSCOPIC ON AND OFF RATE CONSTANTS=Confidence intervals for on / off rate constants: Method>Confidence intervals for on / off rate constants: Results5Cellular potency vs. upper limit of residence time5Lower limit for the on rate constant vs. kinact/KiSummary and conclusionsAcknowledgments  Fonts UsedDesign TemplateEmbedded OLE Servers Slide Titles&_x0..  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUWXYZ[\]_`abcdenRoot EntrydO)PicturesCurrent User^SummaryInformation(+TPowerPoint Document(nxDocumentSummaryInformation8V