Current Computer - Aided Drug Design - Volume 19, Issue 3, 2023

Background: Human parainfluenza viruses type 3 (HPIV-3) through bronchiolitis and pneumonia is a common cause of lower respiratory tract infections. It is the main cause of hospitalization of infants and young children and also one of the main causes of morbidity and mortality in immuno-compromised and transplant patients. Despite many efforts, there is currently no specific anti-HPIV-3 drug or approved vaccine to prevent and control the virus. Identification of HPIV-3 epitopes with the capability of binding to human leukocyte antigen (HLA) class II molecules can be helpful in designing new vaccine candidates against HPIV-3 infection, and also can be useful for the in vitro stimulation and proliferation of HPIV-3-specific T cells for transplant and immunocompromised patients. Objective: To predict and comprehensively evaluate CD4⁺T cell epitope (HLA-II binders) from four main HPIV-3 antigens. Methods: In the present work, we predicted and comprehensively evaluated CD4⁺T cell epitope (HLA-II binders) from four main HPIV-3 antigens, including fusion protein (F), hemagglutininneuraminidase (HN), nucleocapsid (N) and matrix (M) proteins using bio- and immunoinformatics software. The toxicity, allergenicity, Blast screening and population coverage of the predicted epitopes were evaluated. The binding ability of the final selected epitopes was evaluated via a docking study. Results: After several filtering steps, including blast screening, toxicity and allergenicity assay, population coverage and docking study, 9 epitopes were selected as candidate epitopes. The selected epitopes showed high population coverage and docking studies revealed a significantly higher binding affinity for the final epitopes in comparison with the negative control peptides. Conclusion: The final selected epitopes could be useful in designing vaccine candidates and for the treatment of immune-compromised individuals and patients with transplantation.

Objective: The present study aimed to identify new selective inhibitors for acetylcholinesterase, butyrylcholinesterase, monoacylglycerol lipase, beta-secretase, and Asparagine endopeptidase, the targets enzymes in Alzheimer’s disease. Methods: The inhibitory effect of P. atlantica Desf. methanol extracts against AChE were determined using Ellman’s method. The molecular docking study is achieved using Autodock Vina. The structures of the molecules 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3′,5,7- trihydroxy-4′-methoxyflavanone and 5,6,7,4′-tetrahydroxyflavonol-3-O-rutinoside and the five enzymes were obtained from the PubChem database and Protein databank. ADMET parameters were checked to confirm their pharmacokinetics using swiss-ADME and ADMET-SAR servers. Results: P. atlantica Desf. methanol extracts showed a notable inhibitory effect against AChE (IC50 0.26 ± 0.004 mg/ml). The molecular docking results of 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3′,5,7-trihydroxy-4′-methoxyflavanone and 5,6,7,4′-tetrahydroxyflavonol-3-Orutinoside with the five enzymes show significant affinities of these molecules towards Alzheimer disease targets, where they could form several interactions, such as hydrogen bonds and hydrophobic interactions with the studied enzymes. The shortest hydrogen bond is 1.7 A° between masticadienonic acid and Arg128 of the active site of BACE, while the lowest free energy is -11.2 of the complex 5,6,7,4′-tetrahydroxyflavonol-3-O-rutinoside –HuBchE. To the best of our knowledge, these molecules' potential anti-Alzheimer disease effect is studied in this paper for the first time. Conclusion: The docking studies of this work show that 3-methoxycarpachromene and masticadienonic acid, 7-ethoxycoumarin, 3′,5,7-Trihydroxy-4′-methoxyflavanone and 5,6,7,4′-tetrahydroxyflavonol- 3-O-rutinoside have good affinities towards the enzymes involved in Alzheimer pathology, which confirm the ability of these molecules to inhibit the studied enzymes namely: HuAChE, HuBChE, BACE, MAGL, and AEP. These molecules might become drug candidates to prevent Alzheimer's disease.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is currently the leading cause of sudden death in adolescent athletes. Schisandrin is a quality marker of the traditional Chinese medicine Schisandra chinensis, which has an excellent therapeutic effect on HCM, but its pharmacological mechanism remains unclear. Objective: This study aimed to explore the potential and provide scientific evidence for schisandrin as a lead compound against hypertrophic cardiomyopathy. Methods: The drug-like properties of schisandrin were predicted using the SwissADME website. Then, the PharmMapper database was used to predict potential drug targets and match gene names in the Uniprot database. HCM targets were collected from NCBI, OMIM, and Genecards databases and intersected with drug targets. The intersection targets were imported into the STRING database for PPI analysis, and core targets were identified. KEGG and GO enrichment analysis was performed on the core targets through the DAVID database, and all network maps were imported into Cytoscape software for visualization optimization. HCM-related datasets were downloaded from the GEO database to analyze core targets and screen differentially expressed target genes for molecular docking. Results: After the PPI network analysis of the intersection targets of drugs and diseases, 12 core targets were screened out. The KEGG analysis results showed that they were mainly involved in Rap1, TNF, FoxO, PI3K-Akt, and other signaling pathways. After differential analysis, PPARG, EGFR, and MMP3 targets were also screened. The molecular docking results showed that schisandrin was well bound to the protein backbone of each target. Conclusion: This study used network pharmacology combined with differential expression and molecular docking to predict that schisandrin may treat HCM by acting on PPARG, EGFR, and MMP3 targets, and the regulatory process may involve signaling pathways, such as Rap1, TNF, FoxO, and PI3K-Akt, which may provide a valuable reference for subsequent studies.

Background: The south Indian Telugu states will celebrate a new year called ‘Ugadi’ which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. Objective: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. Methods: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. Results: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. Conclusion: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Background: Phosphodiesterase type 5 (PDE5), exclusively specific for cyclic guanidine monophosphate (cGMP), a potential target for the therapy of various diseases, and PDE5 inhibitors could be used as a treatment for erectile dysfunction (ED) or chronic pulmonary hypertension. Objective: In the present study, we carried out an integrated computer-aided virtual screening technique against the natural products in the ZINC database to discover potential inhibitors of PDE5. Methods: Pharmacophore, molecular docking and ADMET (Absorption, distribution, metabolism, excretion and toxicity) properties filtration were used to select the PDE5 inhibitors with the best binding affinities and drug-like properties. The binding modes of PDE5 inhibitors were investigated, and these complexes' stabilities were explored by molecular dynamic simulations and MM/GBSA free energy calculations. Results: Two natural compounds (Z171 and Z283) were identified and may be used as a critical starting point for the development of novel PDE5 inhibitors. The MM/GBSA free energy decomposition analysis quantitatively analyzed the importance of hydrophobic interaction in PDE5- ligands binding. Conclusion: In this study, we identified two novel natural compounds from the ZINC database to effectively inhibit PDE5 through virtual screening. The novel scaffolds of these compounds can be used as the starting templates in the drug design of PDE5 inhibitors with good pharmacokinetic profiles. These results may promote the de novo design of new compounds against PDE5.