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Mass Spectrometry 2019
March 04-05, 2019
Berlin, Germany
Mass Spectrometry
9th Edition of International Conference on
International Journal of Drug Development and Research
ISSN: 0975-9344 Page 24
Understanding inhibitory mechanism of the
selective inhibitors of CdK5/p25 complex by
molecular modelling studies
Amir Zeb, Shailima Rampogu, Minky Son, Ayoung Baek, Sang Hwa
Yoon and Keun Woo Lee
Gyeongsang National University, Republic of Korea
Neurotoxic insults activate calpain, which in turn
produces truncated p25 from p35. p25 forms
hyperactivated CdK5/p25 complex, and thereby
induces severe neuropathological aberrations including
hyperphosphorylated tau, neuroinflammation, apoptosis,
and neuronal death. Inhibition of Cdk5/p25 complex
alleviates aberrant phosphorylation of tau to mitigate
AD pathology. PHA-793887 and Roscovitine have
been investigated as selective inhibitors of Cdk5/p25
with IC50 values 5nM and 160nM, respectively, but
their mechanistic studies remain unknown. Herein,
computational simulations have explored the binding
mode and interaction mechanism of PHA-793887 and
Roscovitine with Cdk5/p25. Docking results suggested
thatPHA-793887andRsocovitinehaveoccupiedtheATP-
bindingsiteof Cdk5andobtainedhighest docking (GOLD)
score of 66.54 and 84.03, respectively. Furthermore,
molecular dynamics (MD) simulation demonstrated
that PHA-793887 and Roscovitine established stable
RMSD of 1.09 Å and 1.48 Å with Cdk5/p25, respectively.
Profiling of polar interactions suggested that each
inhibitor formed hydrogen bonds (H-bond) with catalytic
residues of Cdk5 and could remain stable throughout the
molecular dynamics simulation. Additionally, binding free
energy calculation by molecular mechanics/Poisson–
Boltzmann surface area (MM/PBSA) suggested that
PHA-793887 and Roscovitine had lowest binding
free energies of -150.05 kJ/mol and -113.14 kJ/mol,
respectively with Cdk5/p25. Free energy decomposition
demonstrated that polar energy by H-bond between the
Glu81 of Cdk5 and PHA-793887 is the essential factor
to make PHA-793887 highly selective towards Cdk5/
p25. Overall, this study provided substantial evidences
to explore mechanistic interactions of the selective
inhibitors of Cdk5/p25 and could be used as fundamental
considerations in the development of structure-based
selective inhibitors of Cdk5/p25.
Biography
Amir Zeb is PhD student at Geyongsang National University,
South Korea. His research interest is Computer Aided Drug De-
signing andMolecular Modelling. Mr. Zeb has been exposed to
a number of proteins modelling projects and achieved excel-
lent output. Currently, Mr. Zeb is trying to unveil the mechanis-
tic studies of therapeutics targets in neurological disorders and
their computational inhibition. He has published more than 15
papers in reputed journals.
Amir Zeb, Int J Drug Dev & Res 2019, Volume 11
DOI: 10.21767/0975-9344-C1-005