title: Prospecting for novel plant-derived molecules of Rauvolfia serpentina as inhibitors of Aldose Reductase, a potent drug target for diabetes and its complications.
abstract: Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.
authors.affiliation: Biotechnology Division, Institute of Himalayan Bioresource Technology, Council of Scientific and Industrial Research, Palampur, Himachal Pradesh, India.
authors.forename: Shivalika
authors.initials: S
authors.lastname: Pathania
authors.forename: Vinay
authors.initials: V
authors.lastname: Randhawa
authors.forename: Ganesh
authors.initials: G
authors.lastname: Bagler
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048909:Diabetes Complications / Q000188:drug therapy* / Q000201:enzymology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D006860:Hydrogen Bonding; D006943:Hyperglycemia / Q000201:enzymology / Q000473:pathology; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D012372:ROC Curve; D011926:Rauwolfia / Q000737:chemistry*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010936:Plant Extracts; D000449:Aldehyde Reductase