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E u r o p e a n C o n g r e s s o n
Advanced Chemistry
Advanced Chemistry 2018
J u l y 1 2 - 1 3 , 2 0 1 8
P a r i s , F r a n c e
Page 28
Journal of Organic & Inorganic Chemistry
ISSN: 2472-1123
T
he concept of gene expression is continuously explained with epigenetic
modification. Post-translational histone acetylation and DNA methylation
are dominant epigenetic alterations of the genome. Histone deacetylases
(HDAC) play essential role in this process and therefore are very intensively
investigated drug targets. The alteration in the structure and function of
HDAC isoforms are identified in the pathogenesis of inflammation, cancer,
and neurodegeneration. Eleven human HDAC isoforms are sharing a highly
conserved catalytic domain. Among them, HDAC6 and SIRT2 are important
for a wide range of diseases, due to their unique physiological functions. In
our research, we have applied pharmacophore modelling, virtual screening,
molecular docking and molecular dynamic methodologies for design and
identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the
crystal structure of catalytic domain II of human HDAC6 discovered a wide
binding site essential for the substrate recognition. We have successfully used
these structural features of human HDAC6 catalytic domain II to rationally
design selective HDAC6 inhibitors. Newly published X-ray structures of
selective ligand-SIRT2 complexes have revealed high conformational flexibility
of this enzyme, and gave us more details about mechanism of action of sirtuin
2 inhibitors. Based on these findings we have performed molecular dynamic
study of SIRT2 and tried to explain the conformational changes during enzyme
catalysis. Since small number of selective HDAC modulators have been
reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for
further progress in discovery of epigenetic drugs.
Biography
Katarina Nikolic has completed her PhD from Faculty of Phar-
macy, University of Belgrade. She is an Associate Professor
at Department of Pharmaceutical Chemistry, Faculty of Phar-
macy, University of Belgrade, Serbia. The main areas of her re-
search involve: Molecular Modeling, Pharmacophore Modeling,
Virtual Screening, Molecular Docking and Molecular Dynamic,
Computer-aided Drug Design, Lead Optimisation, Synthesis,
and Chemometry. Her research is currently focused on Discov-
ery of Novel CNS Drugs and Antineoplastic Agents. Her team
has long-lasting research collaboration with several leading Eu-
ropean Universities via few Horison2020/COST projects which
are focused on rational drug design and discovery. She has pub-
lished more than 75 papers in reputed journals.
knikolic@pharmacy.bg.ac.rsComputer-aided drug design of selective histone deacetylase
inhibitors
Katarina Nikolic
1
, Dusan Ruzic
1
, Nemanja Djokovic
1
, Milos
Petkovic
1
, Danica Agbaba
1
, Maija Lahtela-Kakkonen
2
and A
Ganesan
3
1
University of Belgrade, Serbia
2
University of Eastern Finland, Finland
3
University of East Anglia, Norwich, United Kingdom
Katarina Nikolic et al., J Org Inorg Chem 2018, Volume: 4
DOI: 10.21767/2472-1123-C2-005