In silico identification of potential phytochemical inhibitors for mpox virus: molecular docking, MD simulation, and ADMET studies.

The mpox virus (MPXV), a member of the Poxviridae family, which recently appeared outside of the African continent has emerged as a global threat to public health. Given the scarcity of antiviral treatments for mpox disease, there is a pressing need to identify and develop new therapeutics. We investigated 5715 phytochemicals from 266 species available in IMMPAT database as potential inhibitors for six MPXV targets namely thymidylate kinase (A48R), DNA ligase (A50R), rifampicin resistance protein (D13L), palmytilated EEV membrane protein (F13L), viral core cysteine proteinase (I7L), and DNA polymerase (E9L) using molecular docking. The best-performing phytochemicals were also subjected to molecular dynamics (MD) simulations and in silico ADMET analysis. The top phytochemicals were forsythiaside for A48R, ruberythric acid for A50R, theasinensin F for D13L, theasinensin A for F13L, isocinchophyllamine for I7L, and terchebin for E9L. Interestingly, the binding energies of these potential phytochemical inhibitors were far lower than brincidofovir and tecovirimat, the standard drugs used against MPXV, hinting at better binding properties of the former. These findings may pave the way for developing new MPXV inhibitors based on natural product scaffolds. However, they must be further studied to establish their inhibitory efficacy and toxicity in in vitro and in vivo models.

Novel hybrids of thiazolidinedione-1,3,4-oxadiazole derivatives: synthesis, molecular docking, MD simulations, ADMET study, in vitro, and in vivo anti-diabetic assessment.

As compared to standard medicinal compounds, hybrid molecules that contain multiple biologically active functional groups have greater affinity and efficiency. Hence based on this concept, we predicted that a combination of thiazolidinediones and 1,3,4-oxadiazoles may enhance α-amylase and α-glucosidase inhibition activity. A series of novel 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)thiazolidine-2,5-dione derivatives (5a-5j) were synthesized and characterized using different spectroscopic techniques i.e., FTIR, 1H-NMR, 13C-NMR and MS. To evaluate in silico, molecular docking, MMGBSA, and MD simulations were carried out which were further evaluated via in vitro inhibition of α-amylase and α-glycosidase enzyme inhibition assays. In addition, the in vivo study was performed on a genetic model of Drosophila melanogaster to assess the antihyperglycemic effects. The compounds (5a-5j) demonstrated α-amylase and α-glucosidase inhibitory activity in the range of IC50 values 18.42 ± 0.21-55.43 ± 0.66 µM and 17.21 ± 0.22-51.28 ± 0.88 µM respectively when compared to standard acarbose. Based on the in vitro studies, compounds 5a, 5b, and 5j were found to be potent against both enzymes. In vivo studies have shown that compounds 5a, 5b, and 5j lower glucose levels in Drosophila. These compounds could be further developed in the future to produce a new class of antidiabetic agents.

An In-silico Approach: Design, Homology Modeling, Molecular Docking, MM/GBSA Simulations, and ADMET Screening of Novel 1,3,4-oxadiazoles as PLK1inhibitors.

BACKGROUND: Breast cancer is the most commonly diagnosed and major cause of cancer-related deaths in women worldwide. Disruption of the normal regulation of cell cycle progression and proliferation are the major events leading to cancer. Human Polo-like Kinase 1 (PLK1) plays an important role in the regulation of cellular division. High PLK1 expression is observed in various types of cancer including breast cancer. 1,3,4-oxadiazoles are the fivemembered heterocycles, that serve as versatile lead molecules for designing novel anticancer agents and they mainly act by inhibiting various enzymes and kinases. OBJECTIVE: A novel series of 1,3,4-oxadiazole derivatives (A1-A26) were designed and subjected to an in-silico analysis against PLK1 enzyme (PDB ID:1q4k), targeting breast cancer. METHODS: The chemical structure of each compound (A1-26) was drawn using ChemDraw software. The 3D structure model of protein target (PDB ID:1q4k) was built using the SWISSMODEL server. Molecular docking simulation was performed to determine the designed compound's probable binding mode and affinity towards the protein target (PDB ID:1q4k). The designed compounds were subjected to ADME screening, as well as Prime MM/GBSA simulations using Schrodinger suite 2020-4. Furthermore, the safety profile of compounds was examined through the OSIRIS property explorer program and the results were compared with the standard drugs, 5-fluorouracil and cyclophosphamide. RESULTS: Based on the binding affinity scores, the compounds were found selective to target protein 1q4k through hydrogen bonding and hydrophobic interactions. The compounds A11, A12, and A13 were found to have higher G scores and binding free energy values. The ADME screening results were also found to be within the acceptable range. Moreover, the in-silico toxicity prediction assessments suggest that all designed compounds have a low risk of toxicity, and have higher efficiency for the target receptor. CONCLUSION: The study showed that the substitution of electron-donating groups at the various position of the aromatic ring, which is bonded at the second position of the substituted 1,3,4- oxadiazole nucleus resulted in compounds with good binding energy and G score compared to the standard drugs, and hence, they can be further developed as potent PLK1 enzyme inhibitors.

Identification of benzothiazole-rhodanine derivatives as α-amylase and α-glucosidase inhibitors: Design, synthesis, in silico, and in vitro analysis.

A novel series of benzothiazole-rhodanine derivatives (A1-A10) were designed and synthesized, with the aim of developing possible antidiabetic agents and the spectral characterization of these compounds was done using infrared spectroscopy (IR), proton-nuclear magnetic resonance (1 H-NMR), carbon-nuclear magnetic resonance (C13 -NMR), and high resolution mass spectroscopy (HR-MS) techniques. In vitro hypoglycemic potential of the compounds was evaluated by performing α-amylase and α-glucosidase enzyme inhibitory assays. In addition, these compounds were subjected to in silico analysis. Based on the results, compounds A5, A6, and A9 displayed good activity in comparison with the standard acarbose. Based on Lineweaver-Burk plots, it was concluded that compounds A5 and A9 displayed competitive type of enzyme inhibition. Molecular dynamic simulations were conducted to evaluate the stability of the ligand-protein complex by the calculation of the root mean square deviation, root means square fluctuation, and solvent accessible surface area.

Isolation and characterization of ACE-I inhibitory peptides from ribbonfish for a potential inhibitor of the main protease of SARS-CoV-2: An in silico analysis.

Recently, multifunctional fish peptides (FWPs) have gained a lot of attention because of their different biological activities. In the present study, three angiotensin-I converting enzyme (ACE-I) inhibitory peptides [Ala-Pro-Asp-Gly (APDG), Pro-Thr-Arg (PTR), and Ala-Asp (AD)] were isolated and characterized from ribbonfish protein hydrolysate (RFPH) and described their mechanism of action on ACE activity. As per the results, peptide PTR showed ≈ 2 and 2.5-fold higher enzyme inhibitory activity (IC50 = 0.643 ± 0.0011 µM) than APDG (IC50 = 1.061 ± 0.0127 µM) and AD (IC50 = 2.046 ± 0.0130 µM). Based on experimental evidence, peptides were used for in silico analysis to check the inhibitory activity of the main protease (PDB: 7BQY) of SARS-CoV-2. The results of the study reveal that PTR (-46.16 kcal/mol) showed higher binding affinity than APDG (-36.80 kcal/mol) and AD (-30.24 kcal/mol) compared with remdesivir (-30.64 kcal/mol). Additionally, physicochemical characteristics of all the isolated peptides exhibited appropriate pharmacological properties and were found to be nontoxic. Besides, 20 ns molecular dynamic simulation study confirms the rigid nature, fewer confirmation variations, and binding stiffness of the peptide PTR with the main protease of SARS-CoV-2. Therefore, the present study strongly suggested that PTR is the perfect substrate for inhibiting the main protease of SARS-CoV-2 through the in silico study, and this potential drug candidate may promote the researcher for future wet lab experiments.