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

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.

Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory.

Conventional drugs used to treat Tuberculosis (TB) are becoming ineffective due to the occurrence of multiple drug resistant strains of tuberculosis (TB). This has made the TB disease a a serious global health dilemma. Hence, there is desperate necessity for the advancement of new drugs. In this work, the chemical reactivity and bioactivity of several analogs ofpyrazinamide (PZA) were investigated. PZA is one of the first-line of drugs used to treat tuberculosis and is a key contributor to shortening the treatment time for the disease. Chemical reactivity descriptors of pyrazinamide (PZA) and its analogs of acetylsalicyclic acid and salicyclic acid were investigated using conceptual density functional theory in water as a solvent at the MN12SX/Def2TZVP level of theory. Results have shown that all PZA analogs have improved their global and local reactivity indeces as compared to pyrazinamide based on its electronegativity, electrodonating power, electroaccepting power, eletrophilicity, global hardness and dual descriptor condensed fukui indexes. Moreover, their pKa values are slightly higher than PZA. In terms of its drug-likeness, all PZA analogs passed the Lipinski's Rule of Five criteria. Furthermore, their bioactivity scores are significantly better than pyrazinamide indicating good reaction to G-Protein Coupled Receptor (GPCR) ligands, kinase inhibitors, ion channel modulators, nuclear receptor ligands, protease inhibitors and other enzyme targets. Overall, the PZA analogs are found to be promising anti-tuberculosis drugs. Based on global and local reactivity descriptors, pKa and bioactivity scores, PZA analog of 5-n-Octanoylsalicylic acid is the most reactive among the PZA analogs tested.

Investigation of reverse ionic diffusion in forward-osmosis-aided dewatering of microalgae: A molecular dynamics study.

This study aimed to investigate the transport mechanisms of ions during forward-osmosis-driven (FO-driven) dewatering of microalgae using molecular dynamics (MD) simulations. The dynamical and structural properties of ions in FO systems of varying NaCl or MgCl2 draw solution (DS) concentrations were calculated and correlated. Results indicate that FO systems with higher DS concentration caused ions to have lower hydration numbers and higher coordination numbers leading to lower diffusion coefficients. The higher hydration number of Mg2+ ions resulted in significantly lower ionic permeability as compared to Na+ ions at all concentrations (p = 0.002). The simulations also revealed that higher DS concentrations led to higher accumulation of ions in the membrane. This study provides insights on the proper selection of DS for FO systems.