SCREENING AND MOLECULAR DOCKING STUDIES OF NEW NATURAL AGONISTS AGAINST PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA TARGETED TO TREAT OBESITY
Abstract
ABSTRACT
Objective: Obesity was considered as a serious health concern apart from the age group in today's population globally. The percentage of obese people
in the world's population is increasing at a faster rate, and health issues arising due to obesity are gradually increasing. Our present insilico study was
aimed to screen out natural molecules against the peroxisome proliferator-activated receptor (PPAR), especially alpha aids in triggering the obesity.
Methods: Several targets for treating obesity were identified, and one among such promising target was PPAR. Using the insilico applications such as
natural database was screened and the molecules were further evaluated based on their docking score parameter with the receptor.
Results: The docking methodology suggested that two molecules zinc02091671 and zinc02137525 were found to reproduce the similar type of
interactions such as that of the known inhibitor and crystal ligand.
Conclusion: The reported two molecules were found to be promising agonists based on the computational studies and can be advanced the in vitro
based evaluation.
Keywords: Obesity, Peroxisome proliferator-activated receptor, e-pharmacophore, QikProp, Docking.
Downloads
References
REFERENCES
Siraj FM, SathishKumar N, Kim YJ, Kim SY, Yang DC. Ginsenoside F2
possesses anti-obesity activity via binding with PPAR? and inhibiting
adipocyte differentiation in the 3T3-L1 cell line. J Enzyme Inhib Med
Chem 2015;30(1):9-14.
Veeramachaneni GK, Raj KK, Chalasani LM, Bondili JS, Talluri VR.
−
High-throughput virtual screening with e-pharmacophore and molecular
simulations study in the designing of pancreatic lipase inhibitors. Drug
Des Devel Ther 2015;9:4397-412.
Barish GD, Narkar VA, Evans RM. PPAR delta: A dagger in the heart
of the metabolic syndrome. J Clin Invest 2006;116(3):590-7.
Berger JP, Akiyama TE, Meinke PT. PPARs: Therapeutic targets for
metabolic disease. Trends Pharmacol Sci 2005;26(5):244-51.
Evans RM, Barish GD, Wang YX. PPARs and the complex journey to
obesity. Nat Med 2004;10(4):355-61.
Fruchart JC. Peroxisome proliferator - Activated receptor-alpha
(PPARα): At the crossroads of obesity, diabetes and cardiovascular
disease. Atherosclerosis 2009;205(1):1-8.
Chen X, Matthews J, Zhou L, Pelton P, Liang Y, Xu J, et al.
Improvement of dyslipidemia, insulin sensitivity, and energy balance by
a peroxisome proliferator-activated receptor alpha agonist. Metabolism
;57(11):1516-25.
Zhang F, Lavan B, Gregoire FM. Peroxisome proliferator-activated
receptors as attractive antiobesity targets. Drug News Perspect
;17(10):661-9.
Jo J, Gavrilova O, Pack S, Jou W, Mullen S, Sumner AE, et al.
Hypertrophy and/or hyperplasia: Dynamics of adipose tissue growth.
PLoS Comput Biol 2009;5(3):e1000324.
Bourgeois F, Alexiu A, Lemonnier D. Dietary-induced obesity:
Effect of dietary fats on adipose tissue cellularity in mice. Br J Nutr
;49(1):17-26.
Costet P, Legendre C, Moré J, Edgar A, Galtier P, Pineau T. Peroxisome
proliferator-activated receptor alpha-isoform deficiency leads to
progressive dyslipidemia with sexually dimorphic obesity and steatosis.
J Biol Chem 1998;273(45):29577-85.
Ma Y, Wang SQ, Xu WR, Wang RL, Chou KC. Design novel
dual agonists for treating type-2 diabetes by targeting peroxisome
proliferator-activated receptors with core hopping approach. PLoS One
;7(6):e38546.
Loving K, Salam NK, Sherman W. Energetic analysis of fragment
docking and application to structure-based pharmacophore hypothesis
generation. J Comput Aided Mol Des 2009;23(8):541-54.
Salam NK, Nuti R, Sherman W. Novel method for generating structurebased
pharmacophores using energetic
analysis. J
Chem
Inf Model
;49(10):2356-68.
Dixon SL, Smondyrev AM, Rao SN. PHASE: A novel approach to
pharmacophore modeling and 3D database searching. Chem Biol Drug
Des 2006;67(5):370-2.
Samal SK, Routray S, Veeramachaneni GK, Dash R, Botlagunta M.
Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral
cancer. Sci Rep 2015;5:9982.
Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL,
et al. Structural determinants of ligand binding selectivity between the
peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A
;98:13919-24.
Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W.
Protein and ligand preparation: Parameters, protocols, and influence
on virtual screening enrichments. J Comput Aided Mol Des
;27(3):221-34.
Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing
of the OPLS all-atom force field on conformational energetics and
properties of organic liquids. J Am Chem Soc 1996;118:11225-36.
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W.
Prediction of absolute solvation free energies using molecular dynamics
free energy perturbation and the OPLS force field. J Chem Theory
Comput 2010;6(5):1509-19.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT,
et al. Glide: A new approach for rapid, accurate docking and
scoring 1. Method and assessment of docking accuracy. J Med Chem
;47(7):1739-49.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR,
Halgren TA, et al. Extra precision glide: Docking and scoring
incorporating a model of hydrophobic enclosure for protein-ligand
complexes. J Med Chem 2006;49(21):6177-96.
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL,
Pollard WT, et al. Glide: A new approach for rapid, accurate docking
and scoring 2. Enrichment factors in database screening. J Med Chem
;47(7):1750-9.
Published
How to Cite
Issue
Section
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.