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Cancer Congress 2019 Journal of Cancer Immunology &Therapy | Volume 2
Page 19
July 22-23, 2019 | Brussels, Belgium
OF EXCELLENCE
IN INTERNATIONAL
MEETINGS
YEARS
CANCER SCIENCE AND THERAPY
2nd Global Congress on
ANTI-PROLIFERATIVE EFFECT OF POTENTIAL LSD1/COREST INHIBITORS BASED ON
MOLECULAR DYNAMICS MODEL DERIVED FROM ITS INTERACTIONWITH TETRAHY-
DROFOLATE COFACTOR
Hiba Zalloum1, Waleed A Zalloum 2 and Malek Zihlif1
1 The University of Jordan, Jordan
2 American University of Madaba, Jordan
Targeting cancer through epigenetics is a recent era, where a specific gene is manipulated without destroy-
ing 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 utilises 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 dif-
ferent 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 re-
vealed 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 ex-
pressionmodes 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 modelling procedure yielded array of LSD1/CoREST inhibiters
with IC50<5µM, when tested against different cancer cell lines. Three compounds inhibited the growth of PC3
prostate cells with IC50= (2.68, 2.08 and 2.95µM), four of them inhibited the growth of K562 leukaemia cells
with IC50= (1.20, 1.92, 2.70 and 1.20µM) and three of them inhibited the growth of SH-SY5Y neuroblastoma
cells with IC50= (0.27, 0.83 and 4.28µM). These compounds are excellent candidates for further optimization.
J Cancer Immunol Ther 2019, Volume 2