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((6&    #$%## i  $ '"'  1a*bdefNgh;ij=kl6mn.op&qr st uvwxyz {| }~  6!1  *        8 2$9(sW0bt8\X2$K'm0?e"$jS&DmVcSbb "$M=D ;;!Kkg9#2$apYk0Q ><2$(ޞO r~>2$gр~qˤ9:T@2$ֺ]Ju )ǖ./LAb$1.eObNe$Cb$ YAaKhb$ed1]]kzb$X&"E8)0J$Κ2$TQS=%rV 2$lL>_2$s1a6`/m2$faF#E?SJ ,2$j!bG8b$'W`4W9Bb$(KЃPn. Cpb$Ԛ'~KۤDW$%U$$$2$P%ޮO#nda!y"$$$2$L'KUx5$2$SW9-L &2$ht]NoHsǏ(2$ ~u_3*b${# x -b$3ܛ Z|q|ve2"$v+E4c"%1+ b$z"JsXn:\b$7/y]5ә \ $>2$' *[]o 0AA f33@dg4ididȅx: 0ppp@  <4!d!d@ 0t<4BdBd@ 0tg4ddddԒx: 00hp p ʚ;t8ʚ;<4dddd@U 0@r0___PPT10 2___PPT9/ 0?@, ,IC50's are bad for youO =d  (0What is enzyme inhibition on the molecular level:1! $What is the inhibition constant (Ki)8%" !lA thought experiment: Effect of Ki on  fraction bound F7   ;A thought experiment: Titrate 1 nM enzyme, Ki = 0.000001 nMr< >   1Thought experiment, continued: What is the IC50 ?H2-  ,What is the difference between Ki and IC50 ?f-     pImplications for drug discovery:  Hitting the IC50 wall H90   .What is  tight binding * rHow prevalent is  tight binding in a screening campaign?:: 'A word about the Cheng-Prusoff Equation*('  %/ ZA word about the  fold increase in IC50 plotH.%   fAnother word about the  fold increase in IC50 plotH4+  (0.3!Rules of thumb do not always work,"!*1Final word about the  fold increase in IC50 plot: Do not use it.JB) ,2nOther people still use the  fold increase in IC50 plotJ8/ &Review: Measures of inhibitory potency'' nSummary: IC50 s are bad for your drug discovery effortsH8  * (What else is there, other than the IC50?H)%  9Example: Correlation between kinact/Ki and cellular IC50 :  45TKi(app) takes into account  tight binding H+  $%24lThe most  obvious method to get Ki(app) will not workH7"  !Problem: Negative Ki from IC50V  5Solution: Do not use four-parameter logistic equation66 &MSurprise #1: Getting the Ki(app) does not require any additional experimentsN   # .hThe  Morrison Equation for tight binding inhibition555Caveat: Sometimes we need to fit the same data twice66MSurprise #2: Ki(app) can be guessed from a single concentration plus controljN   8 :%The "single-point" method for Ki(app)J&   <68Weighted average to make the initial estimate of Ki(app)f9   1Estimate K*: Example6  &rSurprise #3: We don t need  fully developed IC50 curvesZ: $  'pIt s OK to have at most 20%-30% inhibition if necessary *98  ,#Can we do even better than Ki(app)?X$   -nGetting the  true Ki from a single dose-response curveH8 " #!.nGetting the  true Ki from a single dose-response curveH8 " #(Summary and Conclusions/DeU+"&)+ - / 3 5 =   0` ̙33` ` ff3333f` 333MMM` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>> <4(    6  P  T Click to edit Master title style! !  0     RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S  0L  ``   X*  0  `    l*(    0  `    `* H  0޽h ? ̙33 Default Design0 0 P4@(  4 4 N y y .    x*a00aa 4 N 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 \ Nt ]e]e %     r* AAA  \ T| ]e]e     p* AAA \ T8 ]e]e %    r* AAAH \ 0ηo~ ? ̙3380___PPT10.CP)!U 0 H@ (   X   0A?`mT   6Q   ` Why IC50 s Are Bad for You And Other Surprisesr1333333XB   0D  $   <X  W 4  >Petr Kuzmi , Ph.D. BioKin, Ltd.^      XB   0D@0@H   0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0 ` 5@(  @ @  < "`X   XB @ 0D`X @ 0A?`m\ '@ <D P  Drugs produce their inhibitory action by combining with the enzyme [molecules]. 2R*T (@ <%P`  One molecule of drug will inhibit the activity of one [molecule] of enzyme. 2N9B )@ < ` BEasson, L. H. & Stedman, E. (1936) Proc. Roy. Soc. B 121, 142-151.^C#      =?l  Z 4@ Z,$D  02 *@ <l "`   7E +@ <D "`|@ l `  7I ,@ < Rt "4  3+ZB -@ s *D ZB .@B s *D 2 /@ < "` l  7E 0@ <  "`0R r  7I 1@ <4 d  Cenzyme molecule  2@ <L P p Finhibitor molecule  3@ <t# P Zp Wmolecular complex*   ( 5@ <(  @COMBINATION OF TWO MOLECULES TO FORM AN ENZYME-INHIBITOR COMPLEX`A( 3 3 3 33H @ 0޽h ? ̙33___PPT10+/UD|' = @B D7' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*4@%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*4@D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*4@+  0L0 &)l(  l l  B<5 "`a    XB l 0D`X l 0A?`m' l <8  ADISSOCIATION EQUILIBRIUM CONSTANT OF THE ENZYME-INHIBITOR COMPLEX^B  3 3 3  33 l <? Zz 7E + IRB l s *DnRB l@ s *Dn l <(E ^' OEI^ l 6p l S A T??#" `?*  T2 #l <K $  Z low Ki ( dissociation ) means high binding activity dimension = concentration (moles/liter, M)  good inhibitors have Ki s around 10-9 moles/liter or better (nanomolar)       ,t/}l   )l ,$D 0 $l <\b "`   oU10-3 mili- mM 10-6 micro- mM 10-9 nano- nM 10-12 pico- pM 10-15 femto- fM 10-18 atto-:V       n %l 0"` ` 2 'l < "` @ `  >  (l <Њ ` `  V$ better inhibitorH l 0޽h ? ̙33~___PPT10^+R$DB'  = @B D' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*)l%(+  0L0 D<@&y(  x x  Bd "`R   XB x 0D`X x 0A?`m x <   7E + IRB x s *D  RB x@ s *DPP  x < &9 OEI^  x 6Hl  y@`,$D  0  x2  `A W? ? W  @ p0 xp0n  x 0"`p x < "`pk0 K10-15* x < "`ep 0 K10-12* x < "` p( 0 J10-9* x < "`p0 J10-6*^ x 6 y <   &(Assume equal amounts: [E]0 = [I]0 = 1 nM)&Ll PP  yP P ,$D 0t2 y 6jJ"`  y <X PP ; ~Hat nanomolar [E]0 = [I]0 and femtomolar Ki, there is no free enzyme leftI  , ZB y s *DppH x 0޽h ? ̙33___PPT10+ WpD' = @B Ds' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*y%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*yD' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*yD4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*y%(+-  0L0 \T`&&M (     B "`=   XB  0D`X  0A?`m^   6^  6RB ! s *D  RB " s *DP  # <  p [I]0, nMB  $ <L @2 Oremaining enzyme activityLB % c $D`  RB ( s *D8c0 LB * c $D` RB , s *D8c0 `` LB . c $D`   0 <  vP  50.5 1 <   P  51.0 2 <  ` P  51.5 3 <t  P  52.0 4 <L  @kP  52.5 5 <$  ;P  50.0l P :P,$D 0n2 6 0"`pp 8 <x$ PM NV00 9 <* d@$ 9vRB ; s *D  RB < s *D  RB = s *D   @ B<. ` ,$ 0 T0.5 V02 2 B 6"`` P ,$D 0 C Bo T @ ,$ 0 P[E]00 E Bdz GCHge "`p 0 ,$D 0 Crecall: at [I]0 = [E]0 and Ki << [E]0, there is no free enzyme leftD               ' F <x P  ,$ 0 d[E]0/2Bl @  L@ ,$D 0ZB H s *D  ZB I s *D  n2 K 0"`@0 o M B GH9u "`0 ,$D  0 Arecall: one molecule of inhibitor inhibits one molecule of enzyme^B      H  0޽h ?/ EM ̙33___PPT10+ND'  = @B D@' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(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<*C%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*B%(D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*E%(D' =-o6Bdissolve*<3<*EDA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*F%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*L%(D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*M%(D' =-o6Bdissolve*<3<*M++0+@0 ++0+C0 ++0+E0 ++0+F0 ++0+M0 +H+  0L0 [S&,:(  RB 7 s *D8cP    B "`   XB  0D`X  0A?`m-  <  GCONCENTRATION OF INHIBITOR THAT PRODUCES HALF-MAXIMUM INHIBITORY EFFECT^H 3 3  3 33^   6RB  s *D  RB  s *D   < @ [I]0, nMB   <H `@2, Oremaining enzyme activityLB  c $D  RB  s *D8c LB  c $D RB  s *D8c `` LB  c $D    <  v  50.5  <X    51.0  <D  `  51.5  <8    52.0  <  @k  52.5   <  ;  50.0F P ! pP0n2 " 0"`pp # < PM NV00 $ < @ 9vLB % c $D  LB & c $DLB ' c $D@ @  ( < 0   T0.5 V02 f2 ) 0"` P P  * <  @  P[E]00 , <8    d[E]0/2BF @  - ` @ ZB . s *D  ZB / s *D  n2 0 0"`@0  2 <@& ,F ,$ 0 xIC50 in this case:J ! 3 <$. 0s,$  0  IC50 ~ 0.5 nM6   p 4 <4  ([E]0 = 1 nM Ki = 1 fM = 0.000001 nMh) P   3 6 <> ,$  0 IC50 ~ [E]0 / 2hl P   : P  ,$D 0 8 <D "`P   yIC50 in every case:J  9 <dL "`   IC50 > [E]0 / 2hH  0޽h ? ̙33}u___PPT10U+4D' I = @B DL' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*2%(D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*3%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*3D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*3D{' =%(D#' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*6%(D' =+4 8?dCB1+#ppt_w/2BCB#ppt_xB*Y3>B ppt_x<*6D' =+4 8?\CB#ppt_yBCB#ppt_yB*Y3>B ppt_y<*6D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*:%(++0+20 ++0+30 ++0+60 +   0L0   &< (     B "`    XB  0D`X  0A?`m  <b  'EIC50 DEPENDS ON ENZYME CONCENTRATION AND IS ALWAYS HIGHER THAN THE KiF 3 3 3 3 3 3  3 33C^ , 6 + >A ^?>?#" `? ^^ . 6%%p - S A _??#" `?wq ] _^ 0 6%%p / S A `??#" `?'e  `^ 2 6%%p 1 S A a??#" `? V  ap 3 S A b??#" `?' W  b 7 <p ` J  C competitive  8 <xt   E uncompetitive 9 <,x  0  Fnoncompetitive : <| p 10  B mixed-type  ; <  `& vCha, S. (1975)  Tight binding inhibitors. I. Kinetic behavior Biochem. Pharmacol. 24, 2177-2185.^eB ,B l < 6jJ"`  H  0޽h ? ̙33y___PPT10Y+D='  = @B +68  0L0 &&5(     B@ "`    XB  0D`X  0A?`m  <캰  SNO MATTER HOW TIGHTLY THE INHIBITOR BINDS, THE IC50 CAN NEVER GET LOWER THAN [E]0/2T 3 3 3 3 3  3 3 33  <İ 0; .Assume: competitive [E] = 5 nM [S]0 = KM &  0  LB  c $DLB  c $D@@  <$Ѱ T Ki, nMB$  <װ T IC50, nMB   <ް ' W#1,000 100 10 1 0.1 0.01 0.001$$  <$ ,$ 0 92,002.5  <  p ,$ 0 7202.5  <۰    ,$ 0 622.5  <   ,$ 0 54.5  <D   ,$ 0 52.6   <   ,$ 0 62.52 ! < Y,$  0 72.502 l P B 5BP ,$D  0TB " c $D TB # c $D[ [  $ <$   T Ki, nMB$ % <  !T IC50, nMB  & < B   W#1,000 100 10 1 0.1 0.01 0.001$$ ' <   72,030 ( <    5230 ) <D    450 * <l     :32 + <8  ?  H30.2( , <$    I30.02( - <)   J30.002(t . <. P B  & competitive [E] = 60 nM [S]0 = KM' 0 l   1 ,$D  0t / 6o"`  0 <8    lThe IC50 wall.BCl p0 P 40p P,$D 0e 2 < "`p0  Ki(app) = Ki (1 + [S]/KM)            $ZB 3 s *DPH  0޽h ? ̙334,___PPT10 +uDh'  = @B D#' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*4%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*!%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*5%(D' =%(D' =%(D3' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*1%(D' =-o6Bdissolve*<3<*1++0+0 ++0+0 ++0+0 ++0+0 ++0+0 ++0+ 0 ++0+!0 +  0L0 W O & - (     B^ "`   XB  0D`X  0A?`m2  <a  jTHERE IS NO SUCH THING AS A  TIGHT BINDING INHIBITOR @6 3 33X & 0A ?@ X ' 0A ? l ( 6f>"` RB ) s *DԔ0 RB * s *DԔ` @  + <k 2 e MEXPERIMENTAL CONDITIONS , <,o "`  `   Tight binding kinetics applies when the enzyme concentration in any given assay is greater than the inhibition constant.p|*&\ - B`  *p,$  0 [E] / Ki ~ 1 tight binding is beginning to show up [E] / Ki ~ 10 tight binding is definitely present [E] / Ki ~ 100 highly tight binding [E] / Ki ~ 1000 extremely tight binding ~  7 6 ( !P 65'!H  0޽h ? ̙33___PPT10+,CD'  = @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 +m  0 ' (  x  c $ `   XB  0D`X  0A?`m  <  tEXAMPLE: A PROTEASE CAMPAIGN<  3 3  3  < 0N* E ... NOT SHOWN x  <A h??P& h  <   r: A typical data set: Completely inactive: Tight binding:;;3   <t  l ~ 10,000 compounds ~ 1,100 ~ 4000!   ^   63fjJ*0   <0 @ b*Data courtesy of Celera Genomics 2003-2005++ 3   < @ ,$  0 eabout 4% of compounds4 H  0޽h ? ̙33___PPT10+qU(D'  = @B DD' = @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<* +8+0+ 0 +p  0L0 '% ?(     B "`   XB  0D`X  0A?`m4  < }  \IT DOES NOT TAKE INTO ACCOUNT  TIGHT-BINDING !P/ 3 3# 332  < P  IC50 = Ki (1 + [S]/KM)r      < Pg icompetitive inhibition:6  V  <@ @, Cheng, Y.-Ch. and Prusoff, W. H. (1973)  Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction Biochem. Pharmacol. 22, 3099-3108. Z  L       P@l Fl pp  $pp ,$D 0ZB  s *DԔppp  < & #  !IC50 = Ki (1 + [S]/KM) + [E]0 / 2"      <8' V g  icompetitive inhibition:6    <,  Y  xCha, S. (1975)  Tight binding inhibitor. I. Kinetic behavior Biochem. Pharmacol. 24, 2177-2185. ^fB     ,B  % <P5 "` q&,$D  0 Many J. Med. Chem. papers still use the Cheng-Prusoff equation. If the conditions are tight binding ([E] > Ki) this produces wrong Ki s.| Z >.6H  0޽h ? ̙33A9___PPT10+y4&D' 8 = @B D' = @BA?%,( < +O%,( < +D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*$%(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<*%+8+0+%0 +M 0 5 - P,(    PA ??Object 3z|  tB  L8c?Line 13P L tB  L8c?Line 14 L    <\d "`w Pcompound  X     <h "`p0 Dunnamed kinaseX   <Xm    pCONCLUSION: Compound  X is an ATP insensitive inhibitor`9  l .   0 ,$D  0TB  c $D @TB  c $D 9 @  <4s . 4  ;notXB  0DP  S  w `   `Misuse of the  fold increase plot: A case study11  0{ "`@  Lknown ATP competitorH  0޽h ? I}OPM___PPT10+C)D|' = @B D7' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?\CB#ppt_xBCB#ppt_xB*Y3>B ppt_x<*D' =+4 8?dCB1+#ppt_h/2BCB#ppt_yB*Y3>B ppt_y<*+   0L0  ' (     Bp "`/   XB  0D`X  0A?`ml  <  rIT CAN BE VERY MISLEADING  IF  TIGHT BINDING DOES OCCURr:  3 3 3 3 33/  <p 0v ( WSIMULATED KINASE EXAMPLE: competitive KM(ATP) = 100 M Ki = 0.5 nM [E]0 = 66 nM=     P) f  0A ?"`t @ ~  < tvk @ ,$ 0 \Very shallow slope,  unexpected . [E]0 >> Ki.D/# +l2  6jJ"``B  H  0޽h ? ̙33zr___PPT10R+qD'  = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*+8+0+0 +  0L0 i a @' (     B@ "`!   XB  0D`X  0A?`m  <Ƚ c  {SOMETIMES IT DOES WORK, BUT ...@  3  334  < 0v ( \SIMULATED KINASE EXAMPLE: competitive KM(ATP) = 100 M Ki = 0.5 nM [E]0 = 0.25 nMB     P) f  0A ?"`n @ l2   6jJ"`~. >n   <t tv@ ,$ 0 LSteep slope, as  expected [E]0 < Ki.D' #   <t "`0 ,$D 0 $you don t know if there is  tight binding until you get the Ki(app)^E  ,      =H  0޽h ? ̙33___PPT10+!x9D'  = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bdissolve*<3<* +p+0+ 0 ++0+ 0 + 0 p,(    T` ?Rectangle 2 Z 0 C    TA$ ??Object 6"`P  rB   J|?Line 708 XB   0D`  <    f10-fold increase in IC502   S     lCompound  X is an ATP-competitive inhibitor after all*7 +H  0޽h ? I}OPMy___PPT10Y+D='  = @B +    0L0   , $ (     B "`    XB  0D`X  0A?`m   L ?Text Box 7 NWhat is the  IC50 Rule of Thumb : IC50 for a competitive inhibitor should increase about 10 going from [ATP] = Km to physiological [ATP]. 0 CKCG&8O&8G&8 GG&8G&8&8&8&8&8   N@* ?Text Box 11 What is  Tight Binding : Experimental conditions where the enzyme concentration is comparable with the inhibition constant.|0 C G&8 G&8 G&8G&8 G&8G&8 G&8G&8G&8&8   N: ?Text Box 12L  HAn important fact: The  Rule of Thumb does not apply under the conditions of  Tight Binding . Z`0 CKGGMM   N$C ?Text Box 14R y  VHow do we know this: Many journal articles on  Tight Binding : Morrison (1969), Cha (1974), ..., Kuzmic (2000, 2003, 2011)0|0 ChC tB  LԔ?Line 15  H  0޽h ? ̙33y___PPT10Y+D='  = @B +    0L0 ,  ((       BS "`   XB   0D`X   0A?`m   <W  SOMETIMES IT WORKS AND SOMETIMES IT DOESN T. NO WAY OF TELLING IN ADVANCE IF IT WILL.PX/ 3 3 33f   0A ?"``, l2   6jJ"``. f   0A ?"`N  l2   6jJ"`~ >   < H `Z [E]0 = 0.25 nML     <d `PZ  [E]0 = 66 nML      <m @  VSAME INHIBITOR  DIFFERENT ASSAY CONDITIONS>, H   0޽h ? ̙33y___PPT10Y+D='  = @B +    0L0 , =(     B{ "`   XB  0D`X  0A?`mf   0A#?"`@ l  6Ԕ"``X  0A%? l  68c"`P  i  <Ā tfg4 GChene, P. et al. (2009) BMC Chem. Biol. 9:1, doi:10.1186/1472-6769-9-1 H C  <  tA RECENT PAPER FROM NOVARTIS< 3 33  B GHA "`P  ,$D 0 8What is the main difference between Novartis and ArQule?`9$1H  0޽h ? ̙33zr___PPT10R+WD'  = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bdissolve*<3<*+8+0+0 +  0 "'(  x  c $l `   XB  0D`X  0A?`m   < P2  01. Inhibition constant 2. Apparent K i 3. IC50T1%    <x   hDepends on [S] [E]2 ^B  6DjJP^B  6DjJ ^B   6DjJ    <H  ,   NO YES YESX    <  t ,   NO NO YESX    <ȸ 0 4  OK i0 -   <h 0  K i* = K i (1 + [S]/KM)    C  <h l 0 g@  IC50 = K i (1 + [S]/KM) + [E]/2    ^B  6DjJ    <H V  _Example: Competitive inhibitor$ 2  <  <THE INHIBITION CONSTANT IS AN INTRINSIC MEASURE OF POTENCY: n= 3 3 3  3 33  < @` W%DEPENDENCE ON EXPERIMENTAL CONDITIONS&& X  03f> .^  < 0   :[E] K i: IC50 K i*       < fF0  |DG = -RT log K iP3 333x  <  x :[E] K i: IC50 K i*       < ` @  K"CLASSICAL" INHIBITORS:   <  X  O"TIGHT BINDING" INHIBITORS: H  0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0   `' ~ (     B "`   XB  0D`X  0A?`m   </ .R D<4___PPT9 *You can hit the  IC50 Wall You could be looking at picomolar Ki inhibitors and yet they would look  nanomolar to you, if you are screening at nanomolar [E]. A thousand-fold difference in true vs.  apparent potency. You could get very confused about the  mode of inhibition A competitive inhibitor can give you almost no  fold increase in IC50 if the experiment is done under tight binding conditions. Muddled communication channels within your enterprise The question  What is the biochemical IC50 for compound X? does not make sense for a competitive inhibitor, without specifying [ATP] level._  % 1: :  <6)   ,5  @`Zl     p  ,$D 0`   0   v  <A    vDon t use IC50 as measure of potency in biochemical assays.p<      <LJ "` P/,$D  0 `IC50 s are perfectly good for cell-based assays.d1        H  0޽h ? ̙33{ s ___PPT10S +9ID ' N = @B D ' = @BA?%,( < +O%,( < +Dn' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =+4 8?dCB0-#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<*+8+0+0 +~  0L0 C;' (     B$Y "`pV   X  0A?`m   < "`t fH ,$D 0 5Use intrinsic molecular measures of potency (Ki, ...)n6  -H  0޽h ? ̙33___PPT10+HfDO'  = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(+8+0+ 0 +   0  (5(  x  c $Dm `   XB  0D`X  0A?`m^ ' 6 ( <`o %0  Molecular Underpinnings of Covalent EGFR Inhibitor Potency [...] SUBMITTED>MB3 3%$f - 0A&?"` @ dB .@ <Dm  / Bxw PQ yGinhibition of EGFR-L858R/T790M autophosphorylation in H1975 tumor cellsHH 0 B~ Cf`  Zcell-based potency,  dB 2 <Dm` 3 <  86 okinact 2LB 4 c $D 5 B,  hKi0H  0޽h ? ̙33y___PPT10Y+D='  = @B +  0 jb-,(  ,l" , 68c"` x , c $ `   XB , 0D`X , 0A?`m  , < P2  01. Inhibition constant 2. Apparent K i 3. IC50T1%   , <   hDepends on [S] [E]2 ^B , 6DjJP^B , 6DjJ ^B  , 6DjJ   , <|  ,   NO YES YESX   , <إ  t ,   NO NO YESX   , < 0 4  OK i0 -  , < 0  K i* = K i (1 + [S]/KM)    C , <Լ l 0 g@  IC50 = K i (1 + [S]/KM) + [E]/2    ^B , 6DjJ   , < V  _Example: Competitive inhibitor$ 5 , <  ?IT IS CLOSE TO BEING AN INTRINSIC, MOLECULAR MEASURE OF POTENCYn@ 3 3  3  3 33 , <l @` W%DEPENDENCE ON EXPERIMENTAL CONDITIONS&&  , <  wPT ,$  0 3What do we need to do to move from IC50 to Ki(app)?p4%+H , 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 H @ , $ (  $x $ c $X `   XB $ 0D`X $ 0A?`m^ $ 6p $ S A ??#" `?6  $ <$  jTHIS DOES NOT WORK<  3 3 3 $ >A ?>?#" `? ?@   $ <4    > \  $ < PJ   Could we get the IC50 by our usual method, and then just subtract one half of [E]0? Not in general: - This would work very well for non-tight situations, [E]0 << Ki(app) - In non-tight situation we have IC50 = Ki(app) - However under tight-binding the Ki(app) could become  negative if our enzyme concentration is lower than we think it is. h < 8         > >,'YH $ 0޽h ? ̙33y___PPT10Y+D='  = @B +  0 '(  x  c $x `   XB  0D`X  0A?`mx  <A i????C i  < 4  UFIT TO FOUR-PARAMETER LOGISTIC:  3  <$ fp` J K i* = IC50 - [E] / 2t     <! @: X Data courtesy of Celera Genomics!! 3H  0޽h ? ̙33y___PPT10Y+D='  = @B +  0 (u(  x  c $6 `   XB  0D`X  0A?`mx  <A j????C j  <8   z"FIT TO MODIFIED MORRISON EQUATION:<# 3 3  3  <$?  O0 WeP. Kuzmic et al. (2000) Anal. Biochem. 281, 62-67. P. Kuzmic et al. (2000) Anal. Biochem. 286, 45-50.f           ,,  <B @: X Data courtesy of Celera Genomics!! 3H  0޽h ? ̙33y___PPT10Y+D='  = @B +a  0L0 &@((     B,U "`p   X  0A?`mr  <@X "` ,$D 0 xWe just need to change the way the  IC50 data are analyzed.0=& H  0޽h ? ̙33___PPT10+ksDO'  = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(+8+0+0 +  0L0 `( w(  x  c $d `   XB  0D`X  0A?`mRB  s *D RB  s *D  X  <g 0 ov v initial reaction rate ( Y axis) [I] inhibitor concentration ( X axis)>J"$  <Do  `%  30f2   0"`d   <s ( 2 P  9[I]   0Pq d8 7v   <Lz PT JV0,RB   s *D77X2  0|  X2  0l @ X2  0, ` X2  0a N X2  0 ` X2  0 @ X2  0 0 X2  0yxX2  0 PL X2  0 RB  s *Dl~   <8   9[E]RB  s *D ~~   < h <  30|  s ,A m??#" `?`  m  <0 @7 ^dependent ( Y ) and independent ( X ) variables00`  <h  P  `[E] enzyme concentration V0 control / uninhibited rate ([I] = 0) K* apparent inhibition constantxa &    < 7' p Hmodel parametersH  0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0 (0/(  x  c $< `   XB  0D`X  0A?`m   < X zDPROBLEM: WE NEVER QUITE KNOW WHAT THE ENZYME CONCENTRATION REALLY ISEE 3k ! <̥ "`p0 3Kuzmic, P. et al. (2000) Anal. Biochem. 286, 45-50.4   " < "``@ lFit data to the Morrison Equation while keeping [E]0 constant Ki(app)H-  @RB # s *D ` $ <\ T > Algorithm: RB % s *D@ B & < "`  Ki(app) < [E]0 ?Z    RB ' s *D h ( < "`P  Fit the same data to the Morrison Equation while  floating [E]0 improved Ki(app), [E]0Z%  LRB ) s *D LB * c $D 0 + <T  t 5YESLB - c $D00U RB . s *DU 0U  / < a  4NOi" 0 < "` 0  'Report Ki(app) and optionally also [E]0( H  0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0 (<(     BT "`p   X  0A?`mH  0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0 ( (   x   c $ `   XB   0D`X   0A?`m.   <D  HAN APPROXIMATE VALUE OF THE INHIBITION CONSTANT FROM A SINGLE DATA POINT^I 3  3) 3 3  3   T  ?` \Kuzmic et al. (2000) Anal. Biochem. 281, 62 67/    H A o? ?0 opB  @ H D? `    T  ? @D JV0,pB  @ H D? `    T  ?   IV,   TT  ?0Hm ? "control"     T  ?6&,$ 0 Relative rate Vr = V/V0   pB  @ H D? B    T(  ?p D  K[I],n l @* @   @* @ ,$D 07N ! p   @! ~B   N D?pS   T-  ?`!   Ki = 12 nM t      $6N  P      ~B   N D?P R   T7  ?P   Ki = 9 nM t      $7N @     @ P ~B   N D?@`  S   T@  ? `   Ki = 11 nM t      $6N  *     * @ ~B   N D? P ` R   TLJ  ? * P   Ki = 8 nM t      $z p     ,$D 0p   s ,A p??@   p   TT  ?pD  GSingle-point formula:H   0޽h ? ̙33C;___PPT10+%D'  = @B D' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(+8+0+ 0 +   0L0   @-78+ (  8x 8 c $0c `   XB 8 0D`X 8 0A?`m 8 <A ?|?#" `?`N  RB '8 s *D  @p (8 S A ??#" `?0  p )8 S A ??#" `?0 Ek p *8 S A  ??#" `? `   +8 8A! ??#" `? F5  RB ,8 s *D    -8 >A' ?|?#" `? ]  RB .8 s *D,   LB 08 c $D @ RB 18 s *D<@@ " 28 <n "` 0@ Dweighted average LB 38 c $DP @RB 48 s *D@@ 58 <o 0D  LError Propagation TheoryXr 68 0@0  78 <|x  -  ?Weight:H 8 0޽h ? ̙33y___PPT10Y+D='  = @B +A   0L0 P H )0 (  0x 0 c $( `   XB 0 0D`X 0 0A?`mN 0 C &A i0001 @  0 < @= 71  0 << p 72  0 < r 73   0 < "`f 70   0 <l o M  74   0 < _}  75   0 <    76   0 <̅ 0 Q  77  0 < { 0 ?  78 h 0 <L    8 [I]max = 50 M 4:1 dilution series 8 points + control9          2X 0 0A?  l 0 6>"` 0  0 < "` P   CWeighted average.H 0 0޽h ? ̙33y___PPT10Y+D='  = @B +=  0L0 *(     Bx "`pa   X  0A?`mN  < "` ,$D 0 0... when using the Morrison Equation for Ki(app)21*  )H  0޽h ? ̙33___PPT10+ksDO'  = @B D ' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(+8+0+0 +<  0L0 KC* (  x  c $# `   XB  0D`X  0A?`m`   C 8A"full-006-i0007v n   < &   8 [I]max = 50 M 4:1 dilution series 8 points + control9 2    <\2 &  Ki(app) = (43 2) MVp   <8  PHIGHLY PRECISE Ki(app) EVEN WITH LESS THAN 50% INHIBITION AT MAXIMUM [INHIBITOR]vQ 3 3 3  3 3 3<H  0޽h ? ̙33y___PPT10Y+D='  = @B +  0L0 +<(     B| "`7   X  0A?`mH  0޽h ? ̙33y___PPT10Y+D='  = @B ++  0L0 :2+(  x  c $r `   XB  0D`X  0A?`m  < 8 IIF POSSIBLE, SCREEN AT [SUBSTRATE] MUCH LOWER THAN THE MICHAELIS CONSTANT,J 33 3    < fP  01. Inhibition constant 2. Apparent K i 3. IC50T1%     <`   hDepends on [S] [E]2 ^B   6DjJ<P<^B   6DjJ, ^B   6DjJ,   <@ `   NO YES YESX   <@ ` t   NO NO YESX   <X l0 4 @ OK i0 -  < 0 ` K i* = K i (1 + [S]/KM)    C  <H 0 g  IC50 = K i (1 + [S]/KM) + [E]/2    ^B  6DjJ    <\  W%DEPENDENCE ON EXPERIMENTAL CONDITIONS&&   < ) @ TCompetitive Inhibitor "    < "` @  :At [S] << KM ... Ki(app) H" Ki ,l  68c"`e0H  0޽h ? ̙33y___PPT10Y+D='  = @B +4  0L0 C;, (  x  c $,% `    XB  0D`X  0A?`m  <`' Z xrFOR  NONCOMPETITIVE INHIBITORS Ki(app) = Ki(true) ALWAYS: 3 3  3 3 3 3 3 3 3 3,     <4 fP  01. Inhibition constant 2. Apparent K i 3. IC50T1%    < <   hDepends on [S] [E]2 ^B  6DjJ<P<^B   6DjJ, ^B   6DjJ,    <lB `S  ~ NO NO NOX    <I ` t   NO NO YESX    <P l0 4 @ OK i0   <hV 0 ` ~ K i* = K iX    C  <4^ 0 g  IC50 = K i (1 + [S]/KM) + [E]/2    ^B  6DjJ    <Dj  W%DEPENDENCE ON EXPERIMENTAL CONDITIONS&&   <o )  WNoncompetitive Inhibitor " l  68c"`e H  0޽h ? ̙33y___PPT10Y+D='  = @B +K  0L0 ZR + (  x  c $ X @`H  0޽h ? ̙33y___PPT10Y+D='  = @B + 0 T(  d  c $4     s * 49 f   >@  H  0ηo~ ? ̙33, 0 p D|(  Dd D c $4     D 3 r ss49 f     H D 0ηo~ ? ̙33, 0  &p|(  pd p c $4     p 3 r ss49 f     H p 0ηo~ ? ̙33, 0 P&||(  |d | c $4     | 3 r` ss49 f     H | 0ηo~ ? ̙33, 0 p&|(  d  c $4      3 r ss49 f     H  0ηo~ ? ̙33, 0 &|(  d  c $4      3 rp ss49 f     H  0ηo~ ? ̙33, 0 &|(  d  c $4      3 r ss49 f     H  0ηo~ ? ̙33, 0 &|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33,  0 &|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33,  0 '|(  d  c $4     3 r- ss49 f    H  0ηo~ ? ̙33,  0 0'|(  d  c $4     3 rO ss49 f    H  0ηo~ ? ̙33,  0 P'|(  d  c $4     3 rtY ss49 f    H  0ηo~ ? ̙33,  0 p'|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33  0   '< (  d  c $4      s *z 49 f   & Points to make: Ki is the best, but laborious to get (need to vary both [S] and [I]). Kiapp is the next best. It "costs" as much as getting IC50 (vary [I] only), but is more informative than IC50 (does not depend on [E]). Of these three, IC50 is the least appropriate measure of potency, because... ... for tight binding inhibitors, IC50 shifts with [E]! That means, with a new protocol, a new staff person who changes [E] for some reason, in a different lab, etc., everyone will be getting a different IC50 for the same tight binding inhibitor (e.g., staurosporine) under otherwise identical conditions! Remember, "tight binding" has nothing to do with any particular value of Ki (picomolar, nanomolar, etc.). "Tight binding" is not a property of an inhibitor, but rather a characteristic of experimental conditions: whenever [E] is numerically close to Ki. For example, an inhibitor with Ki = 1 mM is "tight binding" when [E] = 500 nM (this could happen, if your substrate is really slow).@@    F     4   1   .   ^       Q  M           #    ' *   >Y v /H  0ηo~ ? ̙33, 0 '|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33z 0 :2'(  d  c $4   &  s * 49 f   Points to make: How prevalent is tight binding? For how many compounds is IC50 really meaningless? This is a histogram of Kiapp for 10,000+ compounds. Two groups of compounds, centered at about 200 mM and 6 mM, respectively. About 400 (or 4%, or one in 25) are "tight binding", so for one compound out of 25, the IC50 has no meaning. @E@ @   .     H  \     ~H  0ηo~ ? ̙33X 0 '(  d  c $4     0c 49 f   Points to make: Can't fix the problem by the "nave" method: 1. Measure IC50 as usual (four-parameter logistic) 2. Subtract [E]/2 from resulting IC50. PROBLEM! The Kiapp is negative, which is a nonsensical result. We never know exactly what the enzyme concentration really is, so that's why the above "nave" method fails. __________________________ If there is time: Physical meaning of parameters in the four-parameter logistic equation: The Hill exponent (nHill = 1.4 in this case) has not physical meaning at all for a tight binding inhibitor. We do know independently that this compound is very "clean" mechanistically, with exactly 1:1 stoichiometry, a pure competitive inhibitor. The value nHill = 1.4 simply means that the original Hill equation (transformed into the "four parameters logistic") was derived under the assumption that no tight binding occurs! In other words, the basic assumptions of the four-parameter logistic equation are violated. It should not be used for tight binding..@@ A   J        <  t  ^           >&,H  0ηo~ ? ̙33 0 (*(  d  c $4     s *| 49 f   fPoints to make: Here is how to fix the problem: - forget about IC50's completely - forget about the four-parameter logistic equation (4PLE) Instead of 4PLE, use a modification of the Morrison equation (paper #1 above). This will get you the Kiapp directly (it is, of course, positive). As a bonus, you may learn what your enzyme concentration really was. The conditions under which this simultaneous determination of [E] and Kiapp is possible are described in paper #2 above. In this case, the enzyme appears about 65% active (4.5 nM actual concentration, as opposed to 7.0 nM nominal concentration). ^@U@ 7   w  +       0  T         i  $   ,H  0ηo~ ? ̙33  0   0(< (  d  c $4      s *< 49 f   & Points to make: Ki is the best, but laborious to get (need to vary both [S] and [I]). Kiapp is the next best. It "costs" as much as getting IC50 (vary [I] only), but is more informative than IC50 (does not depend on [E]). Of these three, IC50 is the least appropriate measure of potency, because... ... for tight binding inhibitors, IC50 shifts with [E]! That means, with a new protocol, a new staff person who changes [E] for some reason, in a different lab, etc., everyone will be getting a different IC50 for the same tight binding inhibitor (e.g., staurosporine) under otherwise identical conditions! Remember, "tight binding" has nothing to do with any particular value of Ki (picomolar, nanomolar, etc.). "Tight binding" is not a property of an inhibitor, but rather a characteristic of experimental conditions: whenever [E] is numerically close to Ki. For example, an inhibitor with Ki = 1 mM is "tight binding" when [E] = 500 nM (this could happen, if your substrate is really slow).@@    F     4   1   .   ^       Q  M           #    ' *   >Y v /H  0ηo~ ? ̙33, 0 P(|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33, 0 p(|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33, 0 ( |(   d   c $4      3 r ss49 f    H   0ηo~ ? ̙33, 0 (|(  d  c $4     3 rT ss49 f    H  0ηo~ ? ̙33, 0 ($|(  $d $ c $4    $ 3 rh ss49 f    H $ 0ηo~ ? ̙33, 0 0)4|(  4d 4 c $4    4 3 r ss49 f    H 4 0ηo~ ? ̙33,& 0 *|(  d  c $4     3 rd ss49 f    H  0ηo~ ? ̙33,' 0 *|(  d  c $4     3 r, ss49 f    H  0ηo~ ? ̙33,( 0 0+|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33,, 0 +|(  d  c $4     3 r ss49 f    H  0ηo~ ? ̙33,- 0 +|(  d  c $4     3 r` ss49 f    H  0ηo~ ? ̙33,. 0 ,|(  d  c $4     3 r( ss49 f    H  0ηo~ ? ̙33/ 0 4,`,(     xXXXX4?Rectangle 2     # 8F yüyü4?Rectangle 39 3   <MAIN MESSAGE This is one of the earlier ArQule results that will appear (at first sight) to be inconsistent with the most recent data: Here we see a only very slight increase, maybe 25%, going from [ATP]=Km to millimolar [ATP] Later on we will see a ten fold increase. But this is not a contradiction, because the results shown here were obtained under the conditions where the ENZYME CONCENTRATION WAS VERY HIGH. In retrospect, we now know that the Ki is around 0.5 nM. In these AKIP assays the enzyme concentration was 10-20 nM. These are conditions that we call  tight binding . Under those conditions the Rule of Thumb for IC50 increase completely breaks down. A] $4f#  H  0ηo~ ? 3380___PPT10.E`tk0 0 ,((     xXXXX4?Rectangle 2   0  # d yüyü4?Rectangle 39 3   d*MAIN MESSAGE: See slide #12, for FGFR1.  + H  0ηo~ ? 3380___PPT10.E`'wk,1 0 ,|(  d  c $4     3 rl. ss49 f    H  0ηo~ ? ̙33,2 0 ,|(  d  c $4     3 rt ss49 f    H  0ηo~ ? ̙33,3 0 , |(   d   c $4      3 rk ss49 f    H   0ηo~ ? ̙33 4 0   -(< (  (d ( c $4     ( s *h, 49 f   & Points to make: Ki is the best, but laborious to get (need to vary both [S] and [I]). Kiapp is the next best. It "costs" as much as getting IC50 (vary [I] only), but is more informative than IC50 (does not depend on [E]). Of these three, IC50 is the least appropriate measure of potency, because... ... for tight binding inhibitors, IC50 shifts with [E]! That means, with a new protocol, a new staff person who changes [E] for some reason, in a different lab, etc., everyone will be getting a different IC50 for the same tight binding inhibitor (e.g., staurosporine) under otherwise identical conditions! Remember, "tight binding" has nothing to do with any particular value of Ki (picomolar, nanomolar, etc.). "Tight binding" is not a property of an inhibitor, but rather a characteristic of experimental conditions: whenever [E] is numerically close to Ki. For example, an inhibitor with Ki = 1 mM is "tight binding" when [E] = 500 nM (this could happen, if your substrate is really slow).@@    F     4   1   .   ^       Q  M           #    ' *   >Y v /H ( 0ηo~ ? ̙33 5 0   -0< (  0d 0 c $4     0 s * 49 f   & Points to make: Ki is the best, but laborious to get (need to vary both [S] and [I]). Kiapp is the next best. 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