Phytoconstituents of Butterbur (P. japonicus), their metabolic pathway and ability to modulate bone morphogenic protein (BMP) signaling

Figures & data

Figure 1. BMP2 binds to its receptors and activate the SMAD signaling pathway.

Figure 2. Petasites japonicus retrieved from (https://www.gardenfundamentals.com/petasites-japonicus/ last access on 26 Jan 2023).

Figure 3. Reported compounds that can affect bone formation.

Figure 5. The chemical structures of the phenolic compounds from P. Japonicous.

Table 1. Physicochemical properties of compounds that follow Lipinskís and veber rules.

Molecule	MW	MLOGP	Rotatable bonds	HBA	HBD	TPSA	Veber violations	Lipinski violations
Kablicin	430.53	2.75	6	6	1	85.97	0	0
petasinol	352.49	2.4	5	4	1	82.81	0	0
Bakkenolide D	408.51	2.84	6	6	0	104.2	0	0
Bakkenolide IIIa	448.57	3.4	7	6	0	104.2	0	0
Caffeic acid	180.16	0.7	2	3	4	77.76	0	0
Petasiphenol	344.32	0.88	7	4	7	124.29	0	0
Petasitesin A	326.3	1.36	1	4	6	107.22	0	0
Petasitesin B	344.32	0.64	1	5	7	127.45	0	0

Table 2. Pharmacokinetic parameters using Swissadme website.

Molecule	Pgp substrate	Bioavailability score	GI absorption	%ABS	BBB permeant
Kablicin	No	0.55	High	79.34	No
Petasinol	No	0.55	High	80.43	No
Bakkenolide D	No	0.55	High	73.05	No
Bakkenolide IIIa	No	0.55	High	73.05	No
Caffeic acid	No	0.56	High	82.17	No
Petasiphenol	No	0.55	High	66.11	No
Petasitesin A	Yes	0.55	High	72.00	No
Petasitesin B	Yes	0.55	High	65.02	No

Table 3. Pharmacokinetic properties, mutagenicity, tumorigenicity studies, and solubility value using Pre-ADME, DataWarrior and molsoft wbsites.

	Pre-ADME				DataWarrior		Molsoft
Compound Name	^aCaco (nm/sc)	MDCK (nm/sc)	^bHIA (%)	PBP (%)	Mutagenicity	Tumorigenicity	S (mg/l)
Kablicin	35.51	5.25	97.16	93.70	None	None	19.91
petasinol	18.07	8.00	97.06	85.94	None	None	20.64
Bakkenolide D	21.45	6.49	97.77	91.06	None	None	850.12
Bakkenolide IIIa	21.86	0.61	99.22	95.80	None	None	65.79
Caffeic acid	21.10	109.43	82.30	40.29	High	High	3541.88
Petasiphenol	20.52	6.84	79.13	82.40	None	None	5362.92
Petasitesin A	20.97	274.34	82.76	94.66	None	None	1997.94
Petasitesin B	20.90	73.89	67.60	85.92	None	None	6782.68

^a Caco2: Low values were less than 4 nm/s, medium values ranged from 4 to 70 nm/s, and high values were greater than 70 nm/s.

^b HIA: From 0% to 20% poor, 20% to 70%, and 70% to 100% well absorbed.

Figure 6. Binding of BMP-2 to BMPRII and BMPRIA (Miyazono et al. 2010).

Table 4. The binding energy values (kcal/mol) for all compounds.

Compounds	BMPRIA	BMPRII
Agonists	Binding energy (kcal/mol)
Icariin	−10.62	−11.60
Betulinic acid	−7.49	−7.84
Sesquiterpene	Binding energy (kcal/mol)
Petasin	−6.98	−9.58
IsoPetasin	−6.59	−8.24
Neopetasin	−7.19	−10.13
S-Petasin	−6.86	−9.73
Iso-S-Petasin	−6.32	−9.77
Neo-s-petasin	−6.80	−9.53
Petasol	−6.09	−7.85
Isopetasol	−6.04	−7.88
Eremophilene	−5.93	−6.72
Furanopetasin	−6.62	−11.75
Ligularone	−6.22	−7.80
Furanoeremorphilane	−5.68	−7.31
Petasalbin	−6.03	−7.01
Furanofukinol	−6.23	−7.41
Furanofukinin	−5.92	−7.04
Eremophilenolide	−5.48	−7.11
Eremophilanolide	−5.80	−7.98
6-Angeloylfuranofukinol	−6.64	−9.63
Albopetasin	−6.63	−8.60
Eremopetasinorol	−6.08	−7.28
Eremopetasinoron A	−5.89	−7.28
(8R)−2-[(Angeloyl)oxy]eremophil-7(11)-en-12,8-olide	−6.88	−8.46
(8R)−2-[(Tigloyl)oxy]-eremophil-7(11)-en-12,8-olide	−6.54	−8.22
(8R)−2-[(Senecioyl)oxy]eremophil-7(11)-en-12,8-olide	−6.97	−8.22
(8R)−2-[(Methacroyl)oxy]ere-mophil-7(11)-en-12,8-olid	−6.51	−7.92
kablicin	−7.81	−8.36
Petasitin	−6.56	−8.22
Petasinone A	−6.51	−9.50
petasinol	−6.42	−9.42
Bakkenolide A	−5.95	−8.2
Bakkenolide B	−6.35	−7.57
Bakkenolide C	−6.81	−7.81
Bakkenolide D	−7.04	−7.78
Bakkenolide IIIa	−7.82	−9.90
Bakkenolide I	−6.32	−7.92
Bakkenolide V	−6.81	−9.63
Bakkenolide X	−7.11	−9.05
Phenolic compounds	binding energy (kcal/mol)
Chlorogenic acid	−8.71	−12.01
4,5-di-O-caffeoylquinic acid	−10.37	−12.91
1,5-di-O-caffeoylquinic acid	−10.60	−11.80
3,4,5-tricaffeoylquinic acid	−11.70	−13.97
Caffeic acid	−8.83	−12.07
3,5-di-O-caffeoylquinic acid	−9.82	−13.38
Fukinolic acid	−11.31	−14.07
Fukiic acid	−10.08	−12.07
Petasiphenol	−10.88	−13.90
Petaslignolide A	−9.03	−10.53
Petasitesin A	−9.41	−12.76
Petasitesin B	−9.21	−13.50

Table 5. Binding mode of Icariin, Betulinic acid, 1,5-di-O-caffeoylquinic acid, 3,4,5-tricaffeoylquinic acid, Fukinolic acid and Petasiphenol in the active site of BMPIA receptor.

Compound Name	Amino acids involved	Type of bonds	Distance (Å)	The binding energy in kcal/mol	Predicted Ki (µmol)
Icariin	Phe85 Gln86 Asp89 Lys92 Gln86 Arg97 Arg97 Asp89 Asp89 Ser90 His43	Conventional Hydrogen Bond Conventional Hydrogen Bond Carbon Hydrogen Bond Carbon Hydrogen Bond Carbon Hydrogen Bond Pi-Cation Pi-Cation Pi-Anion Pi-Anion Pi-Donor Hydrogen Bond Pi-Donor Hydrogen Bond	3.12 3.07 3.34 3.66 3.52 3.71 3.06 3.90 3.81 4.05 3.60	−10.62	0.016
Betulinic acid	Gln86 His43 Ile62 HIis43 His43	Conventional Hydrogen Bond Pi-Sigma Alkyl Pi-Alkyl Pi-Alkyl	3.00 3.81 5.10 5.02 5.44	−7.49	3.28
Bakkenolide IIIa	Ser90 Ser90 Lys88 Pro91 Phe85 Phe85	Conventional Hydrogen Bond Carbon Hydrogen Bond Alkyl Alkyl Pi-Alkyl Pi-Alkyl	3.36 3.19 4.10 5.09 5.14 5.22	−7.82	1.88
3,4,5-tricaffeoylquinic acid	Asp84 Gln86 Asp89 Asp89 Asp89 Phe85	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Carbon Hydrogen Bond Pi-Donor Hydrogen Bond	2.85 3.16 3.04 3.28 3.69 3.95	−11.70	0.002
Fukinolic acid	Asp89 Gln86 Asp89 Pro91 Phe85 Lys88	Conventional Hydrogen Bond Conventional Hydrogen Bond Carbon Hydrogen Bond Carbon Hydrogen Bond Pi-Donor Hydrogen Bond Pi-Alkyl	3.13 3.31 3.79 3.23 3.82 3.87	−11.30	0.005
Petasiphenol	Arg97 Asp89 Phe85 Asp89 Phe85 Asp89 Asp89 Lys88	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Carbon Hydrogen Bond Pi-Alkyl	3.19 3.25 2.96 3.16 3.03 2.85 3.46 5.47	−10.88	0.01

Table 6. Binding mode and Ki of icariin, betulinic acid, neopetasin, furanopetasin, fukinolic acid, petasiphenol, petasitesin B in active site of BMPII receptor.

Compound Name	Amino acids involved	Type of bonds	Distance (Å)	Docking energy scores in kcal/mol	Predicted Ki (µmol)
Icariin	Ser119 Pro91 Cys94 Gln92 His87 Gly63 His87 Cys94 His95 Pro91 Gln92 His95	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Carbon Hydrogen Bond Carbon Hydrogen Bond Pi-Donor Hydrogen Bond	2.98 2.96 3.18 3.29 3.34 3.10 2.82 3.35 2.89 3.67 3.72 3.37	−11.60	0.003
Betulinic acid	Ser119 Cys94 His95 Pro91 Cys94 Pro91 Pro91	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Alkyl Alkyl Alkyl Alkyl	2.53 2.69 3.10 5.29 4.57 4.20 4.70	−7.84	1.822
Furanopetasin	Asp90 Cys94 Cys94 Ser119 His87 Cys94 Cys94 Ile88 Ile88 Cys94	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Pi-Donor Hydrogen Bond Pi-Sigma Alkyl Alkyl Alkyl Alkyl Pi-Alkyl	2.53 2.64 3.59 3.60 3.84 5.34 5.04 4.83 5.45 5.16	−11.75	0.002
Bakkenolide IIIa	Ser119 Thr65 Cys94 Pro91 Tyr96	Conventional Hydrogen Bond Carbon Hydrogen Bond Sulfur-X Alkyl Pi-Alkyl	2.70 3.61 3.14 3.99 4.57	−9.90	0.056
Fukinolic acid	Thr65 Asp90 His87 Pro91 His87 Glu93 Ser119 His87 His87	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Pi-Cation Pi-Anion Pi-Donor Hydrogen Bond Pi-Donor Hydrogen Bond Pi-Pi Stacked	3.05 2.62 2.89 3.26 3.84 4.78 3.67 3.95 4.13	−14.07	0.00005
Petasiphenol	His87 Gln92 Cys94 His95 His95 His95 Cys94	Conventional Hydrogen Bond Conventional Hydrogen Bond Conventional Hydrogen Bond Pi-Donor Hydrogen Bond Pi-Donor Hydrogen Bond Pi-Pi Stacked Pi-Alkyl	2.85 2.83 2.91 4.02 3.74 4.07 4.21	−13.90	0.00006

Figure 7. 2D and 3D representation of predicted binding mode of Icariin with BMPIA receptor.

Figure 8. 2D and 3D representation of predicted binding mode of Batulinic acid with BMPIA receptor.

Figure 9. 2D and 3D representation of predicted binding mode of Bakkenolide IIIA with BMPIA receptor.

Figure 10. 2D and 3D representation of predicted binding mode of 3,4,5-tricaffeoylquinic acid with BMPIA receptor.

Figure 11. 2D and 3D representation of predicted binding mode of Fukinolic acid with BMPIA receptor.

Figure 12. 2D and 3D representation of predicted binding mode of Petasiphenol with BMPIA receptor.

Figure 13. 2D and 3D representation of predicted binding mode of Icariin with BMPII receptor.

Figure 14. 2D and 3D representation of predicted binding mode of Betulinic acid with BMPII receptor.

Figure 15. 2D and 3D representation of predicted binding mode of Furanopetasin with BMPII receptor.

Figure 16. 2D and 3D representation of predicted binding mode of Bakkenolide IIIa with BMPII receptor.

Figure 17. 2D and 3D representation of predicted binding mode of Fukinolic acid with BMPII receptor.

Figure 18. 2D and 3D representation of predicted binding mode of Petasiphenol with BMPII receptor.

Figure 19. Predicted phase II metabolic pathways and metabolites of Bakkenolide IIIa in humans.

Figure 20. Predicted phase II metabolic pathways and metabolites of Petasiphenol in humans.

Miyazono K, Kamiya Y, Morikawa M. 2010. Bone morphogenetic protein receptors and signal transduction. J Biochem. 147:35–51.

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