In-silico screening and metabolomic profiling identify Naltrindole, a unique isoquinoline from Lentinus squarrosulus (Mont.,1842) mushroom having potent anti-diabetic properties

Abstract

The increasing mortality associated with diabetes mellitus mandates the development of safer alternatives to the currently prescribed drugs that often lead to various health complications. Traditional herbal medicines are safer alternative interventions for managing diabetes mellitus. This study was carried out to determine the anti-diabetic efficacy of Lentinus squarrosulus (Mont.,1842), a medicinal mushroom belonging to the family Polyporaceae. The methanolic extract of Lentinus squarrosulus (Mont.,1842) showed potent antioxidant and anti-diabetic effectuality indicated by robust 2,2-dipheyl-1-picrylhydrazyl (DPPH) radical scavenging activity (EC₅₀ value of 235 ± 4.66 µg/mL) and effective inhibition of the two crucial enzymes associated with diabetes i.e., α-amylase (IC₅₀ value of 317.2 ± 2.50 µg/mL) and α-glucosidase (588.1 ± 8.33 µg/mL). This result encouraged us to carry out the metabolomic profiling of the Lentinus squarrosulus (Mont.,1842) lead extract by liquid chromatography-mass spectrometry (LC-MS), which identified 52 lead mycocompounds. Absorption distribution metabolism excretion toxicity (ADMET) screening affirmed the drug-likeness of only 11 compounds. Robust in-silico screening of the 11 compounds present in Lentinus squarrosulus (Mont.,1842) against five key protein targets involved in diabetes pathophysiology α-amylase, α-glucosidase, GLUT4, IRS1, and GLP1 identified naltrindole, an isoquinoline, as the most effective anti-diabetic mycocompound. Naltrindole shows stronger binding affinities to the five target proteins than prescribed drugs acarbose and metformin. The molecular dynamic simulation study performed suggests the strong interactions of the naltrindole-α amylase complex as evidenced by stable root mean square deviation (RMSD) and root mean square fluctuation (RMSF) plots. Hence, this study reports the identification of naltrindole, resourced from Lentinus squarrosulus (Mont.,1842), a medicinal mushroom, as a promising anti-diabetic drug molecule for the 21st century.