Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Look up keyword
Like this
35Activity
0 of .
Results for:
No results containing your search query
P. 1
Covalent Bonding of Drug to Enzyme

Covalent Bonding of Drug to Enzyme

Ratings:

4.78

(9)
|Views: 1,752|Likes:
Published by achsanuddin
enzyme-ligand non-covalent interactions: competitive inhibition, free energy of binding, covalent binding of drug to enzyme, drug-protein binding forces
enzyme-ligand non-covalent interactions: competitive inhibition, free energy of binding, covalent binding of drug to enzyme, drug-protein binding forces

More info:

Categories:Types, Research, Science
Published by: achsanuddin on Dec 30, 2008
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

11/07/2012

pdf

text

original

 
The Pharmacophore
The functional groups (ionization considered) of a drug and the bioactiveconformation they mustadopt to sustain high-affinity and specific non-covalent interactions with the molecular target.Drug-MT binding forces are the same that stabilize protein tertiary structure:• Hydrogen bonds• Hydrophobic interactionsElectrostatic interactions• Ion-dipole interactions• Dipole-dipole interactions• Charge-transfer complexes
-cationSolvation and intramolecular binding forces:Energy penalty of desolvation of drug and protein MT• Hydrophobic collapseIntramolecular hydrogen bonds- - - - - - - - - - - - - - Aldrich catalog:(
)-(-)-Norepinephrine;
-(aminomethyl)-3,4-dihydroxybenzyl alcohol; (HO)
2
C
6
H
3
CH(CH
2
NH
2
)OH
Wentland-SC-9
HOOONH
3
HH
Bioactive conformation
H
CHEM-4330 - Spring, 2004 - Module 21
Wentland-SC-9k
NNNHNHNONNCH
3
H
3
C
X-Ray Structure of Abl-Tk/STI-571 (1IEP)
Bioactive conformation of STI-571from X-ray coordinates (1IEP)Via Protein Data Bank(http://www.rcsb.org/pdb/)
STI-571(a.k.a. imatinibor Gleevec
®
)
CHEM-4330 - Spring, 2004 - Module 22
Wentland-SC-9m
Protein Structure
Primary
(1
o
) structure:[Amino acid sequence]
NHHNNHHNNHHNNHOP
1
'OP
2
'OOOOOP
3
'P
4
'P
1
P
3
P
2
HNOP
4
Secondary
(2
o
) structure:[Conformation of segments of backbone (e.g.,
-helix,
-sheet)]
Tertiary
(3
o
) structure:[3D arrangement of all atomsIn a protein (e.g., Abl-TK)]
Quaternary
(4
o
) structure:[3D structure of proteins havingmore than one peptide chain(e.g., homodimericHIV protease)]
CHEM-4330 - Spring, 2004 - Module 23
NHHNNHOHOOOCH
3
HHOH
3
NORHO
-
Wentland-SC-9v
Nearly all Natural Amino Acids have a Center of Chirality
+
20 Natural AAs have (
S
)- or L- absoluteconfiguration except Cys (
-) and GlyL-
L-glyceraldehyde (Fischer notation of absolute configuration)(
)- or (
S
)-
Cahn-Ingold-Prelog notationof absolute configuration)The tripeptide, H-Ser-Ala-Phe-OH,drawn in the standard "zig-zag"/N- to C-terminus representation.
CHEM-4330 - Spring, 2004 - Module 24
 
CH
2
-S-S-CH
2
CH
2
H
3
CCHH
3
C
CH
2
OONHH
2
NH
2
N
  • • • • • •  • • • • • •  • • • • • •  • • • • • •  • • • • • •  • • • • • •  • • • • • •  • • • • • •  • • • • • •
CO
2
HH
2
NC OHNDisulfideHydrophobic
-Pleated sheetH-bondElectrostatic
-Helix
Wentland-SC-10
Interactions that Stabilize the Secondary Structure of Proteins
CHEM-4330 - Spring, 2004 - Module 25
Biochim. Biophys. Acta.
1974
,
359
, 298.
1  .3  3  
 1. 4  5  Å
OCH
1.0Å
C
1.23Å
 1.  5  2  Å
C
121.1
o
 
N
121.9
o
123.2
o
115.6
o
118.2
o
119.5
o
H
3
NORHO
-
NOHNNNOOORHR''HR'HHHHNHHCO
2
-
N+OH
+20 Natural AAs have (
S
)- or L- absoluteconfiguration except Cys (
)- and GlyPrimary peptide structure (transoid form)
..
Restricted rotation due to amide resonance
Amino Acid/Peptide Primer 
Amino Acid
Glycine AlanineValineLeucineIsoleucineSerineThreonineCysteineMethioninePhenylalanineTyrosineTryptophanHistidine ArginineLysine Aspartic AcidGlutamic Acid AsparagineGlutamineProline
Wentland-SC-10a
R =
HCH
3
CH(CH
3
)
2
CH
2
CH(CH
3
)
2
(
S
)-CH(CH
3
)CH
2
CH
3
CH
2
OH(
)-CH(OH)CH
3
CH
2
SHCH
2
CH
2
SCH
3
CH
2
C
6
H
5
CH
2
-4-C
6
H
4
OHCH
2
-3-indolylCH
2
-4-imidazolyl(CH
2
)
3
NHC(=NH)NH
2
(CH
2
)
4
NH
2
CH
2
CO
2
HCH
2
CH
2
CO
2
HCH
2
CONH
2
CH
2
CH
2
CONH
2
3 Letter Name
Gly AlaValLeuIleSer Thr CysMetPheTyr TrpHis ArgLys AspGlu AsnGlnPro
1 Letter Name
G AVLISTCMFYWHRKDENQP
+
CHEM-4330 - Spring, 2004 - Module 26
NOHR
Wentland-SC-12c
NOHNHRNOHNOHRRORR
O
-
Glu
O
CHEM-4330 - Spring, 2004 - Module 27
NOOHRNNOOHHNNOOHNHRHRRRNOOHRNNOOHHRNNOHHRRRNHRONOOHRNNOOHHRNNOOHNHRHRRR
Wentland-SC-13c
CH
3
OH
Thr 
CHEM-4330 - Spring, 2004 - Module 28
 
Wentland-SC-13d
Abl-Tk/STI-571 Non-covalent Interactions from 1IEP
NNNNNONNCH
3
H
3
CHHOOCH
2
CH
2
OCHHCH
3
thr315glu286
glu286thr315
IC
50
= 38 nM
CHEM-4330 - Spring, 2004 - Module 29
Wentland-SC-13f 
Enzyme-Ligand Non-Covalent Interactions: Competitive Inhibition
E · I E
+
I
NCC
off 
on
i
=
[
E · I
][
E
] [
I
]
off 
=
on
"Slow tight-binding" inhibitors are characterized by:
-
Slow (relative to diffusion control) "on rate"
-
Very slow "off rate"
-
Displacement of a structured H
2
O from active site
-
Transition state analogue
NCC
(non-covalent complexes)
E · S
[
E · S
]
E · PE
+
S
H
2
OH
2
O
P
+
E
X-H
Substrate
X-H
SubstrateInhibitor 
X-H
Inhibitor 
CHEM-4330 - Spring, 2004 - Module 210
Lineweaver-Burk Plots for Determination of 
i
of a Competitive Inhibitor 
Wentland-SC-14a
1
m
1
mapp
1
m
(1 + [I]/
i
)
   {
0123456789100.10.20.30.40.50.60.70.80.9
 [  I ]=0
 M
   [   I   ] =3   X
   M
  [   I  ] =2  X
  M
  [   I  ]   = 1  X
  M
1[S](mM
-1
)1[
](min/mM)
CHEM-4330 - Spring, 2004 - Module 211
IC
50
Value and Dose Response Curves
Wentland-SC-14b
Inhibitor concentration -
M
   E  n  z  y  m  e   i  n   h   i   b   i   t   i  o  n   (   %   )
1020304050607080901001.0100.100.303.0
IC
50
= 1.0
MIC
50
= 10
M
30100Both inhibitors are equally active;one is 10-fold more potent
IC
50
=
i
1 +[S]
m
When [S] is 10-fold or more below its
m
, then IC
50
~
i
IC
50
= [Inhibitor] that reducesproduct formation by 50%
CHEM-4330 - Spring, 2004 - Module 212

Activity (35)

You've already reviewed this. Edit your review.
1 hundred reads
1 thousand reads
kkk1222 liked this
Anas Dalloul liked this
Sergey Sush liked this
widianingsih liked this
Susmitha Nukala liked this
lanamalay12 liked this
ruma mukherjee liked this

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->