Computation Screening of Multi-Target Antidiabetic Properties of Phytochemicals in Common Edible Mediterranean Plants.
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ABSTRACT:
SUBMITTER: Goulas V
PROVIDER: S-EPMC9269125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) is a global health problem for pigs. PRRSV is highly destructive and responsible for significant losses to the swine industry. Vaccines are available but incapable of providing adequate and long-term protection. As a result, effective and safe strategies are urgently needed to combat the virus. The scavenger receptor cysteine-rich domain 5 (SRCR5) in porcine CD163, non-structural protein 4 (Nsp4), and Nsp10 are known to play significant roles in PRRSV infection and disease development. Therefore, we targeted these proteins to identify multi-target antiviral compounds. To identify potent inhibitors, molecular docking of neem phytochemicals was conducted; three compounds [7-deacetyl-7-oxogedunin (CID:1886), Kulactone (CID:15560423), and Nimocin (CASID:104522-76-1)] were selected based on the lowest binding energy and multi-target inhibitory nature. The efficacy and safety of the selected compounds were revealed through the pharmacokinetics analysis and toxicity assessment. Moreover, 100 ns molecular dynamics (MD) simulation was performed to evaluate the stability and dynamic behavior of target proteins and their docked complexes with selected compounds. Besides, molecular mechanics Poisson-Boltzmann surface area method was used to estimate the binding free energy of each protein-ligand complex obtained from the MD simulations and validate the affinities of selected compounds to target proteins. Based on our analysis, we concluded that the identified multi-target compounds can be utilized as lead compounds for the development of natural drugs against PRRSV. If further validated in clinical studies, these compounds can be used individually or in combination against the virus.
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Project description:INTRODUCTION:Pneumocystis jirovecii is a fungus that causes Pneumocystis pneumonia in HIV and other immunosuppressed patients. Treatment of Pneumocystis pneumonia with the currently available antifungals is challenging and associated with considerable adverse effects. There is a need to develop drugs against novel targets with minimal human toxicities. Histone Acetyl Transferase (HAT) Rtt109 is a potential therapeutic target in Pneumocystis jirovecii species. HAT is linked to transcription and is required to acetylate conserved lysine residues on histone proteins by transferring an acetyl group from acetyl CoA to form e-N-acetyl lysine. Therefore, inhibitors of HAT can be useful therapeutic options in Pneumocystis pneumonia. AIM:To screen phytochemicals against (HAT) Rtt109 using bioinformatics tool. MATERIALS AND METHODS:The tertiary structure of Pneumocystis jirovecii (HAT) Rtt109 was modeled by Homology Modeling. The ideal template for modeling was obtained by performing Psi BLAST of the protein sequence. Rtt109-AcCoA/Vps75 protein from Saccharomyces cerevisiae (PDB structure 3Q35) was chosen as the template. The target protein was modeled using Swiss Modeler and validated using Ramachandran plot and Errat 2. Comprehensive text mining was performed to identify phytochemical compounds with antipneumonia and fungicidal properties and these compounds were filtered based on Lipinski's Rule of 5. The chosen compounds were subjected to virtual screening against the target protein (HAT) Rtt109 using Molegro Virtual Docker 4.5. Osiris Property Explorer and Open Tox Server were used to predict ADME-T properties of the chosen phytochemicals. RESULTS:Tertiary structure model of HAT Rtt 109 had a ProSA score of -6.57 and Errat 2 score of 87.34. Structure validation analysis by Ramachandran plot for the model revealed 97% of amino acids were in the favoured region. Of all the phytochemicals subjected to virtual screening against the target protein (HAT) Rtt109, baicalin exhibited highest binding affinity towards the target protein as indicated by the Molegro score of 130.68 and formed 16 H-bonds. The ADME-T property prediction revealed that baicalin was non-mutagenic, non-tumorigenic and had a drug likeness score of 0.87. CONCLUSION:Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies.
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