POTENT INHIBITORS OF HMG-COA REDUCTASE PHYTOCONSTITUENTS FROM TERMINALIA ARJUNA (ROXB. EX DC.) WIGHT AND ARN. —AN IN SILICO APPROACH THROUGH MOLECULAR DOCKING STUDIES
V. Dhivya Jensi* and P. Ananda Gopu
ABSTRACT
Inhibition of cholesterol synthesis by targeting the enzyme hydroxymethylglutarate coenzyme A (HMG-CoA)
reductase (HMGCR) a rate limiting enzyme in the melvonate pathway has been identified as a promising
approach. The most commonly employed drugs for treatment of hyperlipidemia include HMGCR inhibitors, also
called as statins. Statin users have been identified with some risk factor for muscle-related side effects.CYP450
enzymes, were associated with significantly increased muscle related side effects while on a statin, or even
stopped statin. Even though the inhibitors of HMGCR is evidenced in earlier reports, but their site of metabolism
is not clearly determined. So it is crucial to understand how these potential drugs are metabolized in the body.
Terminalia arjuna stem bark derivatives have been found to possess anti hyperlipidemic activity, 23 compounds of
stem bark extract have been used to build A five-featured 3D-pharmacophore model. pharmacophore consiste of
three hydrogen bond acceptor site (A), and two hydrogen bond donor (D),The model AAADD was used as a query
to find effective activators through database screening and AAADD was validated to check its reliability using
enrichment calculations. The hypothesis was statistically significant with coefficient of correlation r2 = 0.73 and
cross validation correlation coefficient q2= 0.55. External validation result displays significance of the model with
r2 (o) of 0.99 and r2 (m) of 0.51. Quantum mechanical calculations were applied to top five screened compounds.
The stability of the inhibitory reaction was illustrated by MDS studies. Computational methods has been used to
predict the cytochrome P450 sites of metabolism of drug candidates, ADMET properties were predicted to
confirm the safety profile of the identified virtual hits.
Keywords: Terminalia arjuna, HMG-CoA reductase, phytoconstituents, Docking, quercetin.
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