Computational Molecular Biology 2016, Vol.6, No.1, 1-20
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Table 1 Molecules inhibiting the E3 ubiquitin ligases.
Drug
E 3 ligase
Mode of action
References
TAME
APC/C RING E3
ligase
Competitive inhibitor, blocks cyclin degradation
(Zeng and King, 2012)
Thalidomide
Cullin-RING
E3
ligases
Binds ubiquitin substrate , blocks the formation of
substrate-ubiquitin complex
(Liu et al., 2015)
SMER3
SCF E3 ligases
Binds to F-box sub-unit to inhibit its association with
SCF core complex
(Pierce et al., 2010)
Heclin
HECT E3 ligases
Induces conformational changes that result in
oxidation of Cys residue from the active site.
(Mund et al., 2014)
Parthenolide
MDM2 RING E3
ligases
Activates p53 cellular functions
(Gopal et al., 2009)
Nutlin-3
MDM2 RING E3
ligases
p53 stabilization, cell arrest and apoptosis
(Lau et al., 2008)
MLN4924
cullin-RING
E3
ligases
Prevents NEDD8 modification of cullin
(Soucy et al., 2009)
RITA
MDM2 RING E3
ligases
p53 stabilization, cell arrest and apoptosis
(Jones et al., 2012)
Benzodiazepine
MDM2 RING E3
ligases
Distrupt MDM2-p53 binding
(Koblish, 2006)
NSC 6681
MDM2 RING E3
ligases
Distrupt MDM2-p53 binding
(Lu et al., 2006)
Sempervirin
MDM2 RING E3
ligases
Inhibits MDM2 autoubiquitination and MDM2-p53
mediated ubiquitination
(Sasiela et al., 2008)
Tenovin-1
MDM2 RING E3
ligases
Distrupt MDM2-p53 binding by inhibition of the
protein Sirt1-2
(Lain et al., 2008)
Clomipramine
ITCH
Blocks
ITCH
auto-ubiquitylation
and
p73
ubiquitylation
(Rossi et al., 2014)
Pyrrolidine
dithiocarbamate
RING E3 ligases
Distrupts the zinc binding region
(Cvek and Dvorak,
2007)
A01
Smurf1
(HECT)
E3ligase
Attenuates smad degradation
(Y. Cao et al., 2014)
GS143
β-TrCP1 (RING) E3
ligase
Interferes with IkBα ubiquitination
(Hirose et al., 2008)
HLI373
HDM2
ubiquitin
ligases
Inhibits p53 degradation by HDM2
(Yang et al.,2008)
PRT 4165
BMI-1 (RING) E3
ligase
Inhibits ubiquitination of topoisomerase 2α
(Alchanati et al., 2009)
SKPin C1
SkP-1 (RING) E3
ligase
Inhibiton of p27 degradation
(Kitagaki et al., 2008)
SZL P1-41
SkP-2 (RING) E3
ligase
Prevents SkP-1/SkP-2 assembly
( Chan et al., 2013)
SP 141
MDM2 RING E3
ligases
Promotes MDM2 autoubiquitination and degradation
(Wang et al., 2014)
4.2 Computational aided drug discovery
The Fortune magazine published an article titled “Next Industrial Revolution: Designing Drugs by Computer at
MERCK” in 1981(Van, 2007). Since then the computer aided drug designing (CADD) has been on the fore front
of pharmacological drug designing and discovery. Virtual screening (VS) provides the first platform for
short-listing molecules which interact with the particular domain or residues of target protein (Cheng et al., 2012).
With the advancement of computational processing, the method for finding a potent drug candidate is becoming
