High-throughput virtual screening approach of natural compounds as target inhibitors of plasmepsin-II.

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium falciparum parasite responsible for malaria, a disease that is causing deaths on a worldwide scale. Recently, plasmepsin II enzyme has gained much importance as an attractive drug target for the investigation of antimalarial drugs. In this sense, structure-based virtual screening have been utilized as tools in the process of discovering novel natural compounds based on quinoline as potential plasmepsin II inhibitors. Among the 58 quinoline derivatives isolated from different plants was screened by utilizing docking molecular, ADMET approaches, molecular dynamics simulation and MM-PBSA binding free energy. The first step in this work is building the 3 D structures of the plasmepsin II enzyme by using the SWISS-MODEL software. The optimized structures were subjected to virtual screening by Autodock Vina, an entity implicated in PyRx software. 21 were selected based on their binding affinity. The binding modes and interactions of the top-21 selected compounds were evaluated using AutoDock 4.2. Then, the pharmacokinetic proprieties and toxicity of these compounds were evaluated using ADMET analysis. Ten compounds were predicted to have ADMET characteristics with no side effects. Compounds M49 and M53 were found to be potential inhibitors. The stability of the selected two compounds was confirmed by MD simulation and MM/PBSA calculation during 200 ns. This study can be used to predict and to design new antimalarial drugs.Communicated by Ramaswamy H. Sarma.

In silico identification of 1,2,4-triazoles as potential Candida Albicans inhibitors using 3D-QSAR, molecular docking, molecular dynamics simulations, and ADMET profiling.

Fluconazole and Voriconazole are individual antifungal inhibitors broadly adopted for treating fungal infections, including Candida Albicans. Unfortunately, these medicines clinically used have significant side effects. Consequently, the improvement of safer and better therapy became more indispensable. In this study, a set of 27 1,2,4-triazole compounds have been tested as potential Candida Albicans inhibitors by using different theoretical methods. The created comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour maps significantly impacted the development of novel Candida Albicans inhibitors with valuable activities. The mode of interactions between the 1,2,4-triazole inhibitors and the targeted receptor was studied by molecular docking simulation. The proposed new molecule P1 showed satisfied stability in the active pocket of the targeted receptor compared to the more active molecule in the dataset compared to Fluconazole medication. Meanwhile, the binding energy obtained by molecular docking for molecule P1 is - 9.3 kcal/mol compared with - 6.7 kcal/mol for Fluconazole medication. Also, MM/GBSA value obtained by molecular dynamics simulations at 100 ns for molecule P1 is - 33.34 kcal/mol compared with - 15.85 kcal/mol for Fluconazole medication. In addition, molecule P1 showed good oral bioavailability and was non-toxic according to ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Therefore, the results indicated compound P1 might be a future inhibitor of Candida Albicans infection.

Computational approach investigation bioactive molecules from Saussurea Costus plant as SARS-CoV-2 main protease inhibitors using reverse docking, molecular dynamics simulation, and pharmacokinetic ADMET parameters.

SARS-COV-2 virus causes (COVID-19) disease; it has become a global pandemic since 2019 and has negatively affected all aspects of human life. Scientists have made great efforts to find a reliable cure, vaccine, or treatment for this emerging disease. Efforts have been directed towards using medicinal plants as alternative medicines, as the active chemical compounds in them have been discovered as potential antiviral or anti-inflammatory agents. In this research, the potential of Saussurea costus (S. Costus) or QUST Al Hindi chemical consistent as potential antiviral agents was investigated by using computational methods such as Reverse Docking, ADMET, and Molecular Dynamics with different proteases COVID-19 such as PDB: 2GZ9; 6LU7; 7AOL, 6Y2E, 6Y84. The results of Reverse Docking the complex between 6LU7 proteases and Cynaropicrin compound being the best complex, as the same result, is achieved by molecular dynamics. Also, the toxicity testing result from ADMET method proved that the complex is the least toxic and the safest possible drug. In addition, 6LU7-Cynaropicrin complex obeyed Lipinski rule; it formed ≤5 H-bond donors and ≤10 H bond acceptors, MW < 500 Daltons, and octanol/water partition coefficient <5.

In-Silico Molecular Modeling Studies to Identify Novel Potential Inhibitors of HPV E6 Protein.

The etiological agent of some anogenital tract cancers is infection with the high-risk human papillomavirus (HPV). Currently, prophylactic vaccines against HPV have been validated, but the presence of drug treatment directed against the infection and its oncogenic effects remain essential. Among the best drug targets, viral oncoprotein E6 has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6, through interaction with the cellular ubiquitin ligase E6AP, can promote the degradation of p53, a tumor suppressor protein. Therefore, suppression of the creation of the E6-E6AP complex is one of the essential strategies to inhibit the survival and proliferation of infected cells. In the present study, we proposed an in-silico approach for the discovery of small molecules with inhibitory activity on the E6-E6AP interaction. The first three compounds (F0679-0355, F33774-0275, and F3345-0326) were selected on the basis of virtual screening and prediction of the molecules' ADMET properties and docking with E6 protein, these molecules were selected for further study by investigating their stability in the E6 complex and their inhibitory effect on the E6-E6AP interaction by molecular dynamics (MD) simulation. The identified molecules thus represent a good starting point for the development of anti-HPV drugs.