Validation of structural-based virtual screening protocols with the PDB Code 3G0B and prediction of the activity of Tinospora crispa compounds as inhibitors of dipeptidyl-peptidase-IV

Abstract

Introduction: Brotowali (Tinospora crispa) has been traditionally used as an antidiabetic drug. DPP-IV inhibitor as an antidiabetic will increase insulin secretion. It indirectly escalates incretin hormones, such as Glucagon-Like peptide-1 (GLP-1) which depends on glucose. This study predicts potential compounds from the Brotowali plants, such as DPP-IV inhibitors, using the Molegro Virtual Docker (MVD). Materials and methods: Before the molecular docking simulation, internal validation and external validation are necessary. Internal validation was carried out by re-docking the native ligands in the DPP-IV enzyme crystal structure (PDB codes 3G0B, 3W2T, and 3BJM). The external validation was carried out by simultaneous docking of 59 active compounds and 1918 inactive compounds (decoys) from the A Directory of Useful Decoys (DUD) database with PDB code 3G0B on 16 combinations, four search algorithms, and four functions scoring. Results and discussion: The molecular docking simulation was carried out on 50 compounds from the Brotowali plant and alogliptin as standard compounds with PDB code 3G0B. The best results of the docking method validation yielded the RMSD values of 0.43 and EF1% of 20.34 and EF20% of 3.1 (the combination of search algorithm Moldock opti­mizer and scoring function Moldock score). The re-rank score of 5 compounds from the Brotowali plant (Rumphioside C, Borapetoside E, Borapetoside F, Rumphioside I, and 6’-O-Lactoyl Borapetoside B) were -107.7 kcal/mol; -105.4 kcal/mol; -104.2 kcal/mol, and -102.8 kcal/mol. Alogliptin (standard ligands) had a re-rank score of -101.6 kcal/mol. The combination of search algorithms MolDock optimizer and scoring function MolDock score is a valid protocol with a good result. The similarity of the binding sites of Borapetoside E and 6’-O-Lactoyl Borapetoside B is 75% when compared to the alogliptin binding sites (Glu 205, Glu 206, Tyr 547). Conclusion: Based on the re-rank score and binding sites similarity, Borapetoside E and 6’-O-Lactoyl Borapetoside B have potential as an antidiabetic drug with a mechanism of action of DPP-IV inhibitors.