preprints.org > biology and life sciences > biochemistry and molecular biology > doi: 10.20944/preprints202310.1802.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 27 October 2023 / Approved: 27 October 2023 / Online: 27 October 2023 (11:50:06 CEST)

African indigenous herbs and medicinal plants are extensively reported for their protective and therapeutic potential against Diabetes. However, most of the constituent phytochemicals that may account for the therapeutic activity are largely uninvestigated. Exploring novel phytochemical–target interactions in silico could help to provide useful insights into the mechanism underpinning the biological activities of these plants and their constituent phytochemicals. The aim of this study was to explore the interactions of terpene struc-tures previously reported from selected African antidiabetic with two emerging drug targets in diabetes. Structure-based virtual screening was used to screen 107 terpene structures against DPP-4 and PTP1B enzymes. The MD simulation, MM-GBSA free energy calculation and DFT were used to clarify the inter-actions of the in silico hits with the target enzymes. Molecular docking, post-docking Prime MM-GBSA analysis revealed the top terpenes with high binding affinity with the active site regions of DPP-4 and PTP1B. Ensemble docking revealed three triterpenes viz: cucurbitacin B (T1), 6-Oxoisoiguesterin (T4) and 20-Epi-isoiguesterinol (T2) as in silico hits which exhibit strong interaction potential with critical residues that define the catalytic triad (Ser630 and His740); oxyanion cavity (Ser631); hydrophobic S1 pocket (Tyr662) and the charged S2 pocket (Arg125) in the active site region of DPP-4. The interactions of these compounds with DPP-4 exhibited structural stability and conformational flexibility during 100 ns full atomistic MD simulation as indicated by the structure dynamics parameters including RMSD, RoG, SASA and hydrogen bond number. The post-MD MM/GBSA calculations further revealed the stability of the triterpene-DPP-4 complexes. Furthermore, Frontier molecular orbital calculations showed that, the triterpenes possess high interaction potential with the enzyme. The triterpenes showed desirable ADMET properties and drug-likeness. Therefore, cucurbitacin B, 6-Oxoisoiguesterin and 20-Epi-isoiguesterinol are recommended for experimental validation.

diabetes; terpenes; docking; MD simulation; MM-GBSA; DFT

Biology and Life Sciences, Biochemistry and Molecular Biology

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