A pharmacophore screening approach of homeopathic phenols for a renovated design of fragment-optimized Bauhiniastatin-1 as a drug against acromegaly.

OBJECTIVE: Acromegaly is a fatal and chronic disease that is caused by the abnormal secretion of growth hormone (GH) by the pituitary adenoma or pituitary tumor, resulting in an increased circulated concentration of insulin-like growth factors 1 (IGF-1), where in most of the cases it is secreted by a pituitary tumor. Higher levels of GH cause an increase in IGF-1 in the liver leading to multiple conditions such as cardiovascular diseases, glucose imbalance, cancer, and sleep apnea. Medical treatments such as surgery and radiotherapy can be used as the first choice of patients; however, specified human growth hormone control should be an essential treatment strategy due to an incidence rate of 0.2-1.1 yearly. Therefore, the main focus of this study is to develop a novel drug for treating acromegaly by exploiting medicinal plants that have been screened using phenol as a pharmacophore model to identify target therapeutic medicinal plant phenols.

MATERIALS AND METHODS: The screening identified thirty-four pharmacophore matches of medicinal plant phenols. These were selected as suitable ligands and were docked against the growth hormone receptor to calculate their binding affinity. The candidate with the highest screened score was fragment-optimized and subjected to absorption, distribution, metabolism, and excretion (ADME) analysis, in-depth toxicity predictions, interpretation of Lipinski's rule, and molecular dynamic simulations to check the behavior of the growth hormone with the fragment-optimized candidate.

RESULTS: The highest docking energy was calculated as -6.5 K/mol for Bauhiniastatin-1. Enhancing the performance of Bauhiniastatin-1 against the growth hormone receptor with fragment optimization portrayed that human growth hormone inhibition can be executed in a more efficient and better way. Fragment-optimized Bauhiniastatin-1 (FOB) was predicted with high gastrointestinal absorption, a water solubility of -2.61 as soluble, and synthetic accessibility of 4.50, achieving Lipinski's rule of 5, with low organ toxicity prediction and interpreting a positive behavior against the targeted protein. The discovery of a de novo drug candidate was confirmed by the docking of fragment-optimized Bauhiniastatin-1 (FOB), which had an energy of -4,070 Kcal/mol.

CONCLUSIONS: Although successful and completely harmless, present healthcare treatment does not always eradicate the disease in some individuals. Therefore, novel formulas or combinations of currently marketed medications and emergent phytochemicals will provide new possibilities for these instances.