Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants’ potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies.

Sodium-glucose co-transporter 2 (SGLT-2) is a major transport protein responsible for reabsorption of glucose from the kidney back to the bloodstream. Inhibiting this protein effectively lowers the glucose level of diabetic patients; however, the use of synthetic SGLT-2 inhibitors has been linked to some serious adverse effects. There is a need to identify safer alternatives that are equally or more effective as the current inhibitor drugs. Phytochemicals are known for their efficacy as herbal remedies, but these molecules remain underexplored as source of therapeutic agents. In this study, we performed in silico screening to identify potential SGLT-2 inhibitors from the 21 phytochemicals from Centella asiatica. Docking results identified eleven compounds with estimated binding energies comparable to that of known inhibitors drugs. The stability of the complexes was then elucidated using 100 ns MD simulations. From our dynamic binding free energy calculations using MM/PBSA, asiaticoside, betulinic acid, centellasapogenol, methyl brahmate, and rutin exceeded at least one of the binding energies of the reference compounds, which highlights their strong affinity towards SGLT-2. Among the five, betulinic acid, centellasapogenol, and methyl brahmate maintained their structural stability to the same extent as the references and exhibited better oral bioavailability and excellent drug-like properties. Because of these results, it is recommended to prioritize betulinic acid, centellasapogenol, and methyl brahmate in future in vitro and in vivo studies to verify their potential as inhibitor drugs for diabetes therapies. Communicated by Ramaswamy H. Sarma

Through in silico methods, three fungal metabolites, namely cochlactone A, antcamphin M, and methyl ganoderate E, exhibited potential multi-target inhibitory activity against African swine fever virus (ASFV) base excision repair proteins.

The majority of hepatocellular carcinoma cases are caused by infection with hepatitis B (HBV) or C (HCV) viruses. CTNNB1 is the most mutated oncogene in HBV- and HCV-associated tumors. CTNNB1 mutations can lead to β-catenin accumulation, resulting in tumor progression. Small interfering RNAs (siRNAs) can be used to silence CTNNB1 mRNA. After prediction and evaluation, four siRNAs were found to have the highest silencing potential. All four siRNAs had an acceptable GC content, no palindromic sequences, no off-targets, were thermostable, and had accessible target sites. Molecular docking of the siRNAs to Argonaute 2 demonstrated favorable docking scores within the binding pocket for three siRNAs. Molecular dynamics simulations and binding energy calculations demonstrated that the siRNAs steadily remained in the binding pocket. In this study, three siRNAs were successfully designed to silence oncogenic CTNNB1 mRNA as a therapeutic strategy against hepatocellular carcinoma and warrant further in vitro and in vivo validation.

Introduction/Objective: African swine fever virus poses a persistent threat to the global pork industry owing to its severe impact on animal welfare, the economy, and food security. Currently, no antiviral medicines are available, and biosecurity measures, such as quarantine and culling, have proven insufficient, often resulting in further economic losses. Given the widespread impact of ASFV, there is an urgent need to explore and develop new treatment strategies to mitigate its spread. Methods: 1,212 secondary metabolites from brown algae were screened using ADMET profiling. Compounds with favorable properties were selected for molecular docking against A179L, an antiapoptotic protein of ASFV. The top-scoring metabolites were further analyzed through molecular dynamics simulations, principal component analysis (PCA), and binding energy calculations. Results: ADMET profiling identified compounds with drug-like pharmacokinetic properties. Consensus molecular docking using two docking programs predicted the binding poses of the metabolites, and the top ten candidate ligands with the strongest docking scores were selected. We then performed 300 ns molecular dynamics simulations to assess the stability of the protein-ligand complexes, which were further validated through Principal Component Analysis (PCA). Finally, binding energies were estimated using both MMPBSA and MMGBSA approaches, and the key residues involved during binding were identified. All ten final candidate ligands demonstrated stability and favorable binding affinity (-27.78 kcal/mol to -38.58 kcal/mol). Conclusion: Five compounds (CID: 24796376, sargachromanol G, strictaepoxide, CID: 163107957, and saringosterone) with the strongest binding energies are recommended for in vitro and in vivo testing to validate their potential as therapeutic agents against ASFV.

Introduction: African swine fever (ASF) continues to be a significant threat to the global livestock industry due to its severe impact on pig populations. Currently, there are no approved therapeutic agents for the virus, and biosecurity measures such as culling have led to substantial economic losses. In light of its effects on food security and the economy, our study aims to identify potential antiviral compounds from marine fungal metabolites that target the dUTPase enzyme of the African swine fever virus (ASFV). Methods: We screened 4,683 marine fungal metabolites using a series of virtual screening techniques. These included ADMET profiling to assess drug-likeness, consensus molecular docking to predict preferred docking poses and rank the docking scores, 300 ns molecular dynamics (MD) simulations to determine stability, principal component analysis (PCA) to verify simulation convergence, and MMPB(GB)SA analysis to estimate binding affinity. Results: Of the 4,683 compounds, 328 passed our ADMET filter, and the 10 highest-scoring ligands from molecular docking were evaluated for stability and binding affinity against both swine and ASFV dUTPase. Among the candidates, tricycloalternarene C (M1421), derived from Alternaria sp., emerged as a promising candidate. It exhibited excellent drug-likeness, stability, and binding affinity comparable to the three control compounds, while showing less affinity towards the swine dUTPase. Conclusion: Tricycloalternarene C holds potential as a selective inhibitor of ASFV dUTPase. We recommend further experimental validation to confirm its efficacy as an antiviral agent against African swine fever.