Rational screening of peroxisome proliferator-activated receptor-γ agonists from natural products: potential therapeutics for heart failure

Figures & data

Table 1. The ADMET criteria (Gong et al. 2016).

ADMET	Type	Criterion
Caco-2	Absorption	>4 nm/s
HIA	Absorption	>20%
MDCK	Absorption	>25 nm/s
BBB	Distribution	>0
Mutagenicity	Toxicity	Negative
Carcinogenicity	Toxicity	Negative

Figure 1. Structure superposition of docking-modelled PPARγ LBD domain complexes with pioglitazone (a) and rosiglitazone (b) onto their crystal counterparts (PDB: 2xkw and 4ema, respectively), resulting rmsd values of 0.35 and 0.72 Å, respectively. The agonist ligands and domain are shown in stick and ribbon styles, respectively.

Figure 2. Scatter plot of agonistic activity against docking score over nine PPARγ agonists.

Table 2. The nine PPARγ agonists with known agonistic activity.

			Agonistic activity
Agonist	Molecular structure	Docking score (kcal/mol)	EC50 (nM)	pEC50
Pioglitazone		−8.69	280 (Xu et al. 2001)	6.55
Rosiglitazone		−9.34	18 (Xu et al. 2001)	7.74
Farglitazar		−7.78	0.20 (Xu et al. 2001)	9.70
GW409544		−7.20	0.28 (Xu et al. 2001)	9.55
Troglitazone		−6.52	550 (Willson et al. 2000)	6.26
Ciglitazone		−5.43	3000 (Willson et al. 1996)	5.52
E3030		−8.26	34 (Kasai et al. 2008)	7.47
CLX-0921		−7.34	284 (Dey et al. 2003)	6.55
EXP3179		−5.23	17,000 (Schupp et al. 2006)	4.77

Figure 3. PCA mapping of docking-predicted top-100 domain binders onto the first two principal component spaces PC1 and PC2.

Table 3. The eight identified compounds as well as two approved PPARγ agonists.

ZINC	Molecular structure	Docking score (kcal/mol)	EC50 (μM)	Agonistic intensity^c
3846920		−9.18	n.d.	n.d.
4292805		−10.34	2.1 ± 0.29	63%
44179		−9.87	0.35 ± 0.06	78%
3848501		−9.20	n.d.	n.d.
13408172		−9.54	0.084 ± 0.015	116%
901461		−9.12	5.6 ± 0.72	37%
6096559		−9.43	n.d.	n.d.
1595957		−9.86	n.d.	n.d.
Pioglitazone^a		−8.69	0.16 ± 0.023 (0.28^b)	100%
Rosiglitazone^a		−9.34	0.034 ± 0.006 (0.018^b)	124%

^a Two existing PPARγ agonists for comparison purpose.

^b Reported in Ref. (Xu et al. 2001).

^c The percentage of agonistic potency relative to full agonist Pioglitazone at their respective EC₅₀ concentration.

Figure 4. Superposition of computationally modelled conformations of ZINC13408172 and ZINC44179 onto that of pioglitazone in the ligand-binding cavity of PPARγ LBD domain. Comparison of noncovalent interactions at the complex interfaces of PPARγ LBD domain with pioglitazone (a), ZINC13408172 (b) and ZINC44179 (c).

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