Bis-indole alkaloids from Tabernaemontana divaricata as potent pancreatic lipase inhibitors: molecular modelling studies and experimental validation

• Published in: Medicinal chemistry research 2017-06, Vol.26 (6), p.1268-1278
• Main Authors: S. N. C., Sridhar, Mutya, Seshank, Paul, Atish T.
• Format: Article
• Language: English
• Subjects: Alkaloids; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Computer simulation; Disorders; Enzyme kinetics; Hydrophobicity; Indoles; Inhibitors; Leaves; Lipase; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Metabolic disorders; Molecular docking; Molecular dynamics; Molecular modelling; Natural products; Obesity; Organic chemistry; Original Research; Pancreas; Pharmacology/Toxicology
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-017-1836-7

Obesity is the major leading cause of global mortality among metabolic disorders. Orlistat, a pancreatic lipase inhibitor, is the only approved drug of choice for the long term treatment of obesity. However, recent findings reported severe adverse effects with long term administration of orlistat. Plant-based natural products represent a vast reservoir of chemical entities that have the potential to treat various metabolic disorders. In the present study, we have performed a preliminary screening of local flora for pancreatic lipase inhibition assay, which highlighted the methanol extract of Tabernaemontana divaricata leaves (IC 50 of 12.73 µg/mL). Molecular docking of the 38 alkaloids, reported from the leaves of T. divaricata , into the active site of pancreatic lipase led to the identification of furan bridged bis-indole alkaloids viz., Conophylline ( 1 ), Conophyllinine ( 2 ) and Conophyllidine ( 3 ) as potential leads, while Taberhanine ( 4 ), a monomeric indole alkaloid was found to exhibit comparatively poor docking score. Further, molecular docking analysis of the top three molecules ( 1 – 3 ) highlighted the importance of hydrophobic interactions of the dimeric extension with the lid domain of pancreatic lipase, which was not found with 4 . Molecular dynamics simulations of 1–4 in complex with pancreatic lipase, further confirmed the docking results, wherein compound 4 was comparatively less stable (RMSD ≈ 1.5 Å). Liquid chromatography–mass spectrometry analysis of the alkaloid-rich fraction of T. divaricata leaves indicated the presence of 1 , while 2 – 4 were found to be absent. Molecule 1 was tested for pancreatic lipase inhibition potential, where it exhibited potent IC 50 of 3.31 µM, comparable to that of orlistat (IC 50 of 0.99 µM). Enzyme kinetic studies validated the in silico analyses, wherein compound 1 exhibited a competitive reversible inhibition of pancreatic lipase. The present study identified the bis-indole alkaloids of T. divaricata leaves as a new class of potent pancreatic lipase inhibitors.