Application of temperature-dependent and steered molecular dynamics simulation to screen anti-dengue compounds against Marburg virus

Marburg virus infections are extremely fatal with a fatality range of 23% to 90%, therefore there is an urgent requirement to design and develop efficient therapeutic molecules. Here, a comprehensive temperature-dependent molecular dynamics (MD) simulation method was implemented to identify the potential molecule from the anti-dengue compound library that can inhibit the function of the VP24 protein of Marburg. Virtual high throughput screening identified five effective binders of VP24 after screening 484 anti-dengue compounds. These compounds were treated in MD simulation at four different temperatures: 300, 340, 380, and 420 K. Higher temperatures showed dissociation of hit compounds from the protein. Further, triplicates of 100 ns MD simulation were conducted which showed that compounds ID = 118717693, and ID = 5361 showed strong stability with the protein molecule. These compounds were further validated using ΔG binding free energies and they showed: −30.38 kcal/mol, and −67.83 kcal/mol binding free energies, respectively. Later, these two compounds were used in steered MD simulation to detect its dissociation. Compound ID = 5361 showed the maximum pulling force of 199.02 kcal/mol/nm to dissociate the protein-ligand complex while ID = 118717693 had a pulling force of 101.11 kcal/mol/nm, respectively. This ligand highest number of hydrogen bonds with varying occupancies at 89.93%, 69.80%, 57.93%, 52.33%, and 50.63%. This study showed that ID = 5361 can bind with the VP24 strongly and has the potential to inhibit its function which can be validated in the in-vitro experiment. Communicated by Ramaswamy H. Sarma</p

Bioprospecting of Meliaceae family phytomolecules for the treatment of monkeypox virus infection: a QSAR modeling and MD simulation approach

Recent monkeypox virus (MPXV) infections show the risk of MPXV transmission that persists today and the significance of surveillance and quick response methods to stop the virus’s spread. Currently, the monkeypox virus infection is not specifically treated. In this study, QSAR models were designed using known inhibitors of cysteine proteinase from the vaccinia virus, where the Random Forest model and Ridge model had showed the best correlation between predicted and observed EC50. These models were used to screen Maliaceae family phytochemicals against MPXV cysteine proteinase. The compound, IMPHY010637 was detected in top 5 from both the QSAR screening models and showed best docked score (-8.6 kcal/mol) and thus selected for further investigation. Further, the IMPHY010637 showed interaction with the catalytic residue His241 of the protein as reported in earlier studies. The ADMET analysis of the compound showed the acceptable drug-like properties of IMPHY010637. However, these properties could be improved after experimental validation of protein-ligand binding. Both docked complex and poses created in 100 ns MD simulation of the protein-ligand complex showed the presence of multiple hydrogen bonds. RMSD and conformation analysis showed stable binding of IMPHY010637 with the cysteine proteinase of MPXV at its active site. Compared to the known inhibitor, IMPHY010637 showed better binding with the protein as observed by the PCA and MM/GBSA analysis. This study concluded IMPHY010637 as a potential inhibitor for the cysteine proteinase of MPXV using computational methods that could be tested in in-vitro experiments. Communicated by Ramaswamy H. Sarma</p

Table_1_Ethnobotany of Anti-hypertensive Plants Used in Northern Pakistan.docx

<p>Hypertension is one of the most important factors responsible for cardiovascular ailments worldwide. It has been observed that herbal products and alternative herbal therapies played a significant role in decreasing hypertension. The aim of the current study is to provide significant ethnopharmacological information, both qualitative and quantitative on medicinal plants related to hypertension from Northern Pakistan. The documented data were quantitatively analyzed for the first time in this area. A total of 250 participants were interviewed through semi-structured discussions and questionnaires. Quantitative indices including FC (Frequency citation), FIV (Family importance value), RFC (Relative frequency of citation) and DCI (Disease Consensus index) were calculated. A total of 192 plant species, belonging to 77 families were reported to be used in treatment of hypertension in Northern Pakistan. The most dominant life form reported was herbs (54%), with decoction (72 reports) and leaves (55.1%) were commonly utilized plant part. Highest FIV was recorded in Lamiaceae (327 FIV). RFC ranged from 0.08 to 1.08% while DCI varied from 0.233 to 0.000. In this study original data was compared with thirty one previous national and international published papers from neighboring region to compare the medicinal uses and obtain some novel plant species. About 42% of the medicinal plant species were reported for the first time in treatment of hypertension in comparison to these 31 published papers. Different phytochemical activities of antihypertensive plants were also reported from literature. This research work documents the traditional knowledge of medicinal plants usage and provides baseline in designing clinical trials and pharmacological analysis for treatment of hypertension.</p