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Euro Pharma Chemistry & Future Pharma 2019
Volume 08
Research & Reviews: Journal ofPharmaceutical Analysis | ISSN : 2320-0812
June 27-28, 2019 | Amsterdam, Netherlands
12th World congress on
Joint Event
4
th
Pharmaceutical Chemistry Conference Future Pharma
Anti-proliferative effect of potential LSD1/CoREST inhibitors based on molecular dynamics
model derived from its interaction with tetrahydrofolate cofactor
Hiba Zalloum
1
, Waleed A Zalloum
2
and
Malek Zihlif
1
1
The University of Jordan, Jordan
2
American University of Madaba, Jordan
T
argeting cancer through epigenetics is a recent era, where a specific gene is manipulated without
destroying it. Lysine-specific demethylase 1 (LSD1) is one of the enzymes that are associated with
chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3
tail. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to
accept CH2 from the demethylation process. Many studies showed that inhibiting LSD1 could potentially
be used to treat cancer epigenetically. The fact that the cofactor is best bound to the active site inspired us to
explore its interactions to LSD1/CoREST enzyme complex utilizing molecular dynamics simulation, which
aids designing novel and potent inhibitors. Also, the conformational existence of the enzyme complex bound
to the cofactor has been investigated. According to the molecular dynamics simulation study, LSD1/CoREST
complex is present in open and closed conformations. Furthermore, tetrahydrofolate was found to bind to two
binding sub-sites with different binding modes. The model derived from the molecular dynamics simulation
study and the key contacts to the active site were used in the subsequent structure based drug design and in-
silico screening, which revealed a number of new chemical entities with a potential inhibitory effect of LSD1/
CoREST complex. In-silico mining on National Cancer Institute (NCI) database identified 60 promising and
structurally diverse inhibitors. The cytotoxic activities of these compounds were tested against different cancer
cell lines with different expression modes of LSD1/CoREST complex such as leukaemia K562, prostate
cancer PC3 and neuroblastoma SH-SY5Y. All compounds were also tested against normal fibroblast cells
to study their selectivity against cancer cells. Applying the abovementioned molecular modeling procedure
yielded array of LSD1/CoREST inhibiters with IC50 <5 µM, when tested against different cancer cell lines.
Three compounds inhibited the growth of PC3 prostate cells with IC50=(2.68, 2.08 and 2.95 µM), Four of
them inhibited the growth of K562 leukaemia cells with IC50=(1.20, 1.92, 2.70, and 1.20 µM) and three of
them inhibited the growth of SH-SY5Y neuroblastoma cells with IC50=(0.27, 0.83 and 4.28 µM). These
compounds are excellent candidates for further optimization.
Pharmaceutical Analysis 2019, Volume 08