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Asian Journal of Biomedical and Pharmaceutical Sciences | ISSN: 2249-622X | Volume 8
&
Joint Event
Chemistry and Organic Chemistry
Biomedicine & Pharmacotherapy
International Conference on
8
th
World Congress on
October 22-23, 2018 | Frankfurt, Germany
Notes:
Virtual screening platform on structure based pharmacophore hypothesis to design potential human
LDH-A inhibitors against cancer
Vibhu Jha
University of Pisa, Italy
H
uman Lactate dehydrogenase A (LDH-A) has been
identified as a potential therapeutic target in cancer
cell metabolism as it catalyzes conversion of pyruvate
to lactate in presence of cofactor NADH. Based on latest
medicinal chemistry research on LDH-A inhibitors, we
have developed a pharmacophore model using consisting
of four pharmacophore features: two H-bond acceptors
and two hydrophobic aromatic rings (keeping one H-bond
acceptor mandatory for activity). The presence of co factors
such as Zn
2+
and NADH on crystal structure of LDH-A was
also taken into consideration. The pharmacophore model
was subjected to Phase Virtual Screening on 1,500,000
commercially available compounds of Enamine database.
Selected compounds were filtered out from structure-based
pharmacophore search method. Crystal structure of LDH-A
(PDB ID: 5W8K) with cofactor NADH was taken for further
docking studies. In order to find the most accurate docking
pose, self docking analysis on selected protein with 13
docking programs was performed, followed by the selection
of 10 docking programs for further post-docking studies that
showed docking pose within an average RMSD of 1.5 Å. The
successful docked compounds were subjected to consensus
docking platfrom in order to search the common docking
pose amongst all docking procedures and compounds
were selected from consensus level 6, 7 and 8 which
showed similar binding mode as of co-crystallized ligand.
Ligand-protein complexes of filtered compounds were
then analyzed through a final post-docking filter Molecular
Dynamics (MD) Simulations with AMBER 16 software in
order to confirm the stability of the predicted binding
modes. The final compounds from overall study are currently
under biochemical studies for LDH-A inhibitory activity.
e:
vibhu.jha@farm.unipi.itChemistry and Biomedicine 2018, Volume 8
DOI: 10.4066/2249-622X-C4-012