A molecular fragment from the triterpenoids oleanolic acid and ursolic
acid can provide new scaffolds to design new antitumor and
antileishmanial drugs
Zottis, A.*; Marchetto, R.
*zottisad@gmail.com
Department of Biochemistry and Chemical Technology – Instituto de Química - Universidade Estadual Paulista Júlio de
Mesquita Filho – Unesp – Rua Professor Francisco Degni, 55 – Bairro Quitandinha - Araraquara – SP – Brasil.
Keywords: Type I topoisomerase, triterpenoids, ursolic acid, oleanolic acid, docking, molecular dynamics simulation.
Introduction
Type I topoisomerase from human (hTopoI) and
Leishmania species (LTopoI) are attractive targets to
develop drugs against cancer and leishmaniasis,
respectively, and some triterpenoids, i.e. betulinic
1,2
acid inhibits both enzymes.
We describe the
docking and simulations of molecular dynamics with
these enzyme targets and the natural products
ursolic acid (UA) and oleanolic acid (OA), other
3,4
triterpenoids that also inhibit these topo targets.
The results strongly suggest that a fragment of these
derivatives could be a useful structure to develop a
novel class of hTopoI and LTopoI inhibitors through
fragment-based design.
Apparently, both ligands showed higher affinity for
hTopoI than for LTopoI, according to our modeling
study. The values of binding energy are showed in
Table 1.
Table 1. Estimative of binding energy (Kcal/mol)
obtained for the best pose of every docked
complex.
hTopoI
LTopoI
OA
-8.25
-7.23
UA
-8.34
-7.3
Conclusions
Results and Discussion
The best pose from 10 complexes obtained for every
docking procedure between both ligands and these
targets are showed in Figure 1.
A
B
Although both oleanolic acid and ursolic acid inhibit
both hTopoI and LTopoI, our models suggest a little
higher affinity for human enzyme.
Molecular dynamics provided substantial evidence
that molecular fragments from these inhibitors
bearing the acid group can provide a scaffold to
design more selective inhibitors by a fragment-based
approach. This can be particularly useful to discover
a new class of TopoI inhibitors to develop new
anticancer and antileishmanial drugs.
Acknowledgements
We thank to São Paulo Research Foundation
(FAPESP) for the financial support (process number
2012/00360-4).
____________________
C
D
Figure X. Best pose obtained during the docking
between UA and OA tripterpenoids with hTopoI
(PDB ID 1K4T) and LTopoI (PDB ID 2B9S). A) OA
and hTopoI; B) OA and LTopoI; C) UA and
hTopoI; d) UA and LTopoI.
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