In the current study, an effort was undertaken to analyze the physicochemical characteristics of MYG formulation. In this study special attention was created towards the GGS compound which is major constituent that plays a significant role in lipid lowering activity. GGS is C21H28O2 with a Molecular weight of 312.45, LogP IS 4.6436, 02acceptors, 0 donors, 34.14 TPSA value.
In-silico ADMET analysis is a precise method to estimate whether the chemical entity has its minimum criteria to fall under the acceptable pharmacokinetics and pharmacodynamics characteristic. Based on their ADMET profile, GGS was projected to have low toxicity concerns and high bioavailability. Molecular property and toxicity prediction of selected compounds were established. The pharmacokinetic parameters of GGS are given in Table 2.
Table 2
Pharmacokinetic Parameters of guggulsterone
Parameters | Guggulsterone |
Water solubility (log mol/L) | -4.931 |
CaCo2 permeability (log Papp in 10− 6 cm/s) | 1.294 |
Intestinal absorption (% Absorbed) | 99.655 |
Skin Permeability (log Kp) | -2.465 |
VDss (Human) (log L/kg) | 0.158 |
Fraction Unbound (Fu) | 0.001 |
Substrate | CYP3A4 |
Total clearance (log ml/min/kg) | 0.61 |
AMES Toxicity | NO |
Oral route Acute Toxicity (LD50) (mol/kg) | 1.843 |
Oral route chronic toxicity (log mg/kgbw/day) | 1.769 |
Hepatotoxicity | YES |
Skin sensitization | NO |
Minnow toxicity (log mM) | 0.312 |
In this study, we have chosen GGS targeted against hyperlipidaemia. The targets of GGS &HLD generated from swiss targets online portal and Target related to hyperlipidaemia were generated from DisGeNET database and 15 overlapping targets[AR,NR3C2,NR1I2,CYP19A1,FABP1,NPC1L1,CCR5,HSD11B1,ESR1,ESR2,BCHE,PTGS1,ALOX5,HMGCR,PIK3CA] were identified. The network status is depicted in Fig. 3. The KEGG pathway enrichment analysis indicated that 14 pathways related to signalling pathways were directly correlated with the basic steroid nuclease and that confirms a mechanism of action of GGS in the progression of HLD. The final targets are the Prolactin signaling pathway, Endocrine resistance, Estrogen signaling pathway, Breast cancer, Metabolic pathways, Ovarian steroidogenesis, Aldosterone-regulated sodium reabsorption, Fat digestion and absorption, Pathways in cancer, Regulation of lipolysis in adipocytes,Steroid hormone biosynthesis, Arachidonic acid metabolism, Fc epsilon RI signalling pathway, GnRH secretion. PIK3CA pathway was reported with 1.75strength and 03 gene count which interlinks the existing network confirming that Prolactin influenced the degree of inflammatory response in atherosclerotic lesions and demonstrated a high level of prolactin receptor expression in atherosclerotic individuals. It suggests that prolactin may be expressed strongly in hyperlipidaemia. PPAR signalling pathway: PPAR, PPAR, and PPAR/ prevented cholesterol buildup and atherogenic inflammation, respectively. Adipocytokine is involved in the development of plaque, vascular inflammation, and endothelial dysfunction, all of which are hyperlipidaemia pathologies. The major targets related to GGS & HLD are given in Table 3.
Table 3
Term description | Observed gene count | Background gene count | Strength | False discovery rate | matching proteins in final network (labels) |
Prolactin signaling pathway | 3 | 69 | 1.75 | 0.0071 | PIK3CA,ESR2,ESR1 |
Endocrine resistance | 3 | 95 | 1.61 | 0.0089 | PIK3CA,ESR2,ESR1 |
Estrogen signaling pathway | 3 | 133 | 1.47 | 0.0157 | PIK3CA,ESR2,ESR1 |
Breast cancer | 3 | 145 | 1.43 | 0.0157 | PIK3CA,ESR2,ESR1 |
Metabolic pathways | 6 | 1447 | 0.73 | 0.0268 | PIK3CA,HMGCR,PTGS1, HSD11B1,ALOX5,CYP19A1 |
Ovarian steroidogenesis | 2 | 50 | 1.72 | 0.0268 | ALOX5,CYP19A1 |
Aldosterone-regulated sodium reabsorption | 2 | 37 | 1.85 | 0.0268 | PIK3CA,NR3C2 |
Fat digestion and absorption | 2 | 41 | 1.8 | 0.0268 | NPC1L1,FABP1 |
Pathways in cancer | 4 | 517 | 1 | 0.0268 | PIK3CA,ESR2,AR,ESR1 |
Regulation of lipolysis in adipocytes | 2 | 54 | 1.68 | 0.0277 | PIK3CA,PTGS1 |
Steroid hormone biosynthesis | 2 | 59 | 1.65 | 0.0298 | HSD11B1,CYP19A1 |
Arachidonic acid metabolism | 2 | 61 | 1.63 | 0.0298 | PTGS1,ALOX5 |
Fc epsilon RI signaling pathway | 2 | 66 | 1.6 | 0.0298 | PIK3CA,ALOX5 |
GnRH secretion | 2 | 63 | 1.62 | 0.0298 | PIK3CA,ESR2 |
3.1 Molecular docking assessment:
The Molecular docking studies were performed for the GGS and atorvastatin against the cytochrome P450, cytochrome 3A4, PDB id: 5TE8. The structures were designed, and the binding interaction energies were calculated using score techniques. A more negative range indicates the effective confirmation of bounding ligand-target. GGS showed a stronger binding affinity when compared with atorvastatin. The docking score for GGS was − 9.28 kcal/mol and positive control atorvastatin − 8.26kcal/mol. The GGS show good binding interaction when compared with positive control atorvastatin. Followed by the network analysis the docking parameters confirm the Lipid-lowering potential of GGS.