Identification of PPARγ ligands with One-dimensional Drug Profile Matching

Figures & data

Figure 1 Summary of the oDPM.

Notes: (A) Summary of the oDPM: IP generation and IP similarity calculations. Drugs A and X are docked to the 149 members of the protein set. Their respective IPs (with color-coded energy values ranging from green to red [ie, from lower DS to higher DS values, respectively]) are compared, and a pairwise similarity value is calculated. Based on these values, similarity lists are created for each drug, containing the remaining set of molecules in a decreasing order of similarity. (B) Summary of the effect prediction method using oDPM. In the first step, similarity lists are created for each drug in the reference set (containing eight compounds in this case) and cut at a predefined IP distance value (d). Then, drugs appearing multiple times in the truncated lists are collected. Reference drugs appearing in each other’s similarity lists are omitted. The remaining drugs are predicted to possess the given effect.
Abbreviations: DS, docking score; IP, interaction pattern; oDPM, One-dimensional Drug Profile Matching.

Table 1 Generic drugs showing PPARγ receptor ligand affinity after the One-dimensional Drug Profile Matching screening

Bromfenac	Dantrolene	Entacapone	Ethacrynic acid	Ketorolac
Nonsteroidal anti-inflammatory drug	Ryanodine receptor antagonist	Catechol-O-methyl transferase inhibitor	Na^+-K^+-Cl^− cotransport inhibitor	Nonsteroidal anti-inflammatory drug
Lubiprostone	Nitazoxanide	Suprofen	Tiaprofenic acid	Tolmetin
PGE1 analogue, activates CIC-2 chloride channels	Antiprotozoal agent, interfere with the electron transfer	Nonsteroidal anti-inflammatory drug	Nonsteroidal anti-inflammatory drug	Nonsteroidal anti-inflammatory drug

Notes: Detailed description of the selection is described in the text. The original, known pharmacological action/indication of these drugs is also indicated.

Abbreviations: PGE1, prostaglandin E1; CIC-2, chloride channel.

Table 2 Interaction pattern distance values of the predicted ten generic drugs

Ketorolac	Entacapone	Tolmetin	Nitazoxanide	Suprofen	Ethacrynic acid	Bromfenac	Lubiprostone	Dantrolene	Tiaprofenic acid
0	1.389	1.004	1.550	1.045	1.188	1.181	2.520	1.775	1.031	Ketorolac
	0	1.258	1.516	1.157	1.103	1.418	2.320	1.483	1.343	Entacapone
		0	1.504	0.867	1.197	1.199	2.348	1.619	0.914	Tolmetin
			0	1.639	1.458	1.676	2.756	2.066	1.492	Nitazoxanide
				0	1.228	1.174	2.384	1.668	0.939	Suprofen
					0	1.516	2.545	1.517	1.298	Ethacrynic acid
						0	2.380	1.958	1.328	Bromfenac
							0	2.326	2.534	Lubiprostone
								0	1.917	Dantrolene
									0	Tiaprofenic acid

Figure 2 The effect of (A) bromfenac, (B) nitazoxanide, (C) suprofen, and (D) lubiprostone (10⁻⁸ M to 10⁻⁵ M) on FABP4/aP2 gene expression in MM6 cell lines. Rosiglitazone (10⁻⁸ M to 10⁻⁶ M) was used as a positive control. *Indicates significant changes from the vehicle-treated (DDDT or ethanol) control.

Abbreviations: RNA, ribonucleic acid; DDDT, dimethyl sulfoxide; FABP4/ap2, fatty acid-binding protein 4/adipocyte protein; MM6, Mono Mac 6.

Figure 3 Relative fold change in the mRNA expression in response to the highest dose of various drugs.

Notes: Lubiprostone elicited the greatest induction in mRNA expression, but its effect was not dose-dependent. Suprofen and nitazoxanide evoked a similar increment in mRNA expression, but only nitazoxanide showed a dose-dependent relationship. The effect of bromfenac was also dose-dependent, but it induced the smallest enhancement in mRNA expression.
Abbreviation: mRNA, messenger ribonucleic acid.

Table 3 The effect of 8-day nitazoxanide treatment (50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day) on the fasting blood glucose and plasma insulin level, on the resting blood pressure, as well as on body weight

	Fasting blood glucose (mmol/L)	Fasting plasma insulin (μIU/mL)	Mean arterial blood pressure (mm Hg)	Body weight (g)
Health, vehicle	4.3 ± 0.3*	5.8 ± 0.4*	124 ± 11	341 ± 22
HFD, vehicle	4.37 ± 0.7*	5.3 ± 0.3*	129 ± 12	384 ± 26
HFD + STZ, vehicle	8.7 ± 1.3	17.5 ± 5.5	129 ± 8	345 ± 35
HFD + STZ + NTX 50 mg/kg	8.5 ± 1.5	14.3 ± 4.7	122 ± 12	366 ± 21
HFD + STZ + NTX 100 mg/kg	8.1 ± 1.4	17.2 ± 4.4	126 ± 13	372 ± 33
HFD + STZ + NTX 200 mg/kg	7.3 ± 1.2*	18.7 ± 5.2	127 ± 10	370 ± 30

Note:

* Indicates significant changes from the HFD + STZ and vehicle-treated groups.

Abbreviations: HFD, high-fat diet; STZ, streptozotocin; NTX, nitazoxanide.

Figure 4 The effect of 8-day NTX treatment (50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day per os twice a day) on the GIR, ISI, and on the MCRI. *Indicates statistically significant changes from the HFD + STZ and vehicle-treated groups.

Abbreviations: HFD, high-fat diet; STZ, streptozotocin; NTX, nitazoxanide; GIR, glucose infusion rate; ISI, insulin sensitivity index; MCRI, metabolic clearance rate of insulin; per os, via the mouth.