An <i>in silico</i> analysis of the interaction of marine sponge-derived bioactive compounds with type 2 diabetes mellitus targets DPP-4 and PTP1B

Abstract

Type 2 diabetes is a medical condition involving elevated blood glucose levels resulting from impaired or improper insulin utilization. As the number of type 2 diabetes cases increases each year, there is an urgent need to develop novel drugs having new targets and/or complementing existing therapeutic protocols. In this regard, marine sponge-derived compounds hold great potential due to their potent biological activity and structural diversity. In this study, a small library of 50 marine sponge-derived compounds were examined for their activity towards type 2 diabetes targets, namely dipeptidyl peptidase-4 (DPP-4) and protein tyrosine phosphatase 1B (PTP1B). The compounds were first subjected to molecular docking on protein models based on their respective co-crystal structures to assess binding free energies (BFE) and conformations. Clustering analysis yielded BFE that ranged from 24.54 kcal/mol to −9.97 kcal/mol for DPP-4, and from −4.98 kcal/mol to −8.67 kcal/mol for PTP1B. Interaction analysis on the top ten compounds with the most negative BFE towards each protein target showed similar intermolecular interactions and key interacting residues as in the previously solved co-crystal structure. These compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling to characterize drug-likeness and combining the results from these analyses, (S)-6’-debromohamacanthin B was identified as a potential multi-target inhibitor of DPP-4 and PTP1B, having favorable protein interaction, no Lipinski violations, good gastrointestinal (GI) tract absorption, blood-brain barrier (BBB) penetration, and no predicted toxicity. Finally, the interaction of (S)-6’-debromohamacanthin B with the two proteins was validated using molecular dynamics simulations over 100 ns through RMSD, radius of gyration, PCA, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) confirming favorable interactions with the respective proteins. Communicated by Ramaswamy H. Sarma A 50-compound library previously reported from marine sponges was docked to putative T2DM targets, DDP-4 and PTP1B.(S)-6’-debromohamacanthin B was identified as a probable dual-targeting compound based on binding interactions and ADMET evaluation.Interaction of (S)-6’-debromohamacanthin B with DPP-4 and PTP1B was validated by MD simulations. A 50-compound library previously reported from marine sponges was docked to putative T2DM targets, DDP-4 and PTP1B. (S)-6’-debromohamacanthin B was identified as a probable dual-targeting compound based on binding interactions and ADMET evaluation. Interaction of (S)-6’-debromohamacanthin B with DPP-4 and PTP1B was validated by MD simulations.</p