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Identification of Unique anti- Atherosclerosis Inhibitors from Herbal plants – A Computational Approach

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Title Identification of Unique anti- Atherosclerosis Inhibitors from Herbal plants – A Computational Approach
 
Creator Dubey, Amit
 
Contributor Ramteke, Prof. (Dr.) Pramod W
 
Subject Ginkgo biloba; Chymase; Herbal Nutraceutical; Screening; Molecular docking; inhibitor; cardiovascular diseases, Biogenic compounds, pharmacophore, chamomile, binding energy, validation, active site, sensitivity, specificity, Matricin, chlorogenic acid, Catalytic pocket, Dendogram, Density Function Theory, Homo, Lumo, Frontier Orbital, Quantum Mechanics, Quantum Energy, Electrostatic potential, Electropositive potential, Electronegative potential
 
Description Thesis on “Identification of Unique anti- Atherosclerosis Inhibitors from Herbal plants – A Computational Approach”submitted in Partial Fulfillment of the Requirement for the award of the Degree of Doctor of Philosophy in Bioinformatics by Amit Dubey.
The human chymase (EC 3.4.21.39) is a serine protease abundant in secretory granules of
mast cells, that possesses chymotrypsin-like cleavage specificity and is responsible and is
involved in the synthesis of angiotensin II from its precursor. Moreover, it is also
responsible for the activation and conversion of transforming growth factor-β (TGF-β) and
matrix metalloproteinase (MMP)-9 precursors to their active forms. Chymase-induced
activation of TGF-b and MMP-9 shows significance in cardiovascular disease. Since a link
between atherosclerosis and chymase has been proved, specific chymase inhibitors are
actively searched to develop new therapeutic treatments for cardiovascular diseases,
considering also that chymase has no enzymatic activity in normal tissues. Therefore,
specific chymase inhibitors may not have effects on any other target in normal tissues. The
use of natural products has been an integral part of the treatment of different diseases
throughout the world since past centuries. Many plants with potential therapeutic activity
were widely used as natural medicines with negligible undesired effects. Therefore, the
search for new active compounds from natural sources is gaining interest in the scientific
community, and the application of novel approaches to an old science could result in the
discovery of valuable compounds useful to develop innovative drugs. The aim of the
present study was to search for novel inhibitors of chymase enzyme from natural sources or
inspired by nature, using a computational approach that allowed us to screen databases of
compounds and to predict which molecules can be able to bind to chymase with a good
affinity and selectivity against other human serine proteases (kallikrein, elastase and
tryptase). Among the selected compounds obtained from ZINC Biogenic database,
ii
“ZINC22061412 and ZINC04416136"are predicted to bind human chymase with a binding
energy comparable, or even better, with respect to the one predicted for known inhibitors.
Among the compounds selected from ginkgo biloba and chamomile plants, all show a
negative binding energy, suggesting a potential ability to interact with the enzyme, but the
absolute values are often higher with respect to those of known inhibitors, indicating a less
favorable interaction. Combining previous computational studies, at the final stage were
performed on natural compounds subsets from different nutraceutical sources, highlighting
Density Functional Theory-based quantum mechanical studies on good candidate screened
by generated pharmacophore models. Other electronic properties were calculated such as
LUMO, HOMO, and locations of molecular electrostatic potentials, for identification of
potent hits that can bind to various bioactive conformations available in the active site of
enzyme. Finally four best candidate, Cynarine, Curcumin, Scutellarin, and Ginkgolic acid
show a predicted binding energy equal or even better than those predicted for many known
chymase inhibitors. The analysis of the complexes with the best predicted energies shows
that these molecules can interact with the key residues involved in substrate binding and
catalysis. Moreover, several compounds are able to interact with chymase with a good
selectivity towards the other tested serine proteases, since the predicted binding energy for
these last enzymes is in some cases significantly higher with respect to that for chymase. In
conclusion, the selected molecules can become novel candidates for the therapeutic action
in the context of cardiovascular diseases, making them good candidates for further
experimental studies to characterize their activity in vitro and in vivo. Our results also
shows a possible explanation of their inhibitory mechanism and important structural
insights which extend my expertise for drug designing against enzyme targets, enhancing
the possibility for the potential development of future drugs.
 
Date 2016-12-14T14:38:23Z
2016-12-14T14:38:23Z
2016
 
Type Thesis
 
Identifier http://krishikosh.egranth.ac.in/handle/1/90146
 
Language en
 
Format application/pdf
 
Publisher Sam Higginbottom Institute of Agriculture, Technology & Sciences (SHIATS)