Deep learning application detecting SARS-CoV-2 key enzymes inhibitors.

The fast spread of the COVID-19 over the world pressured scientists to find its cures. Especially, with the disastrous results, it engendered from human life losses to long-term impacts on infected people's health and the huge financial losses. In addition to the massive efforts made by researchers and medicals on finding safe, smart, fast, and efficient methods to accurately make an early diagnosis of the COVID-19. Some researchers focused on finding drugs to treat the disease and its symptoms, others worked on creating effective vaccines, while several concentrated on finding inhibitors for the key enzymes of the virus, to reduce its spreading and reproduction inside the human body. These enzymes' inhibitors are usually found in aliments, plants, fungi, or even in some drugs. Since these inhibitors slow and halt the replication of the virus in the human body, they can help fight it at an early stage saving the patient from death risk. Moreover, if the human body's immune system gets rid of the virus at the early stage it can be spared from the disastrous sequels it may leave inside the patient's body. Our research aims to find aliments and plants that are rich in these inhibitors. In this paper, we developed a deep learning application that is trained with various aliments, plants, and drugs to detect if a component contains SARS-CoV-2 key inhibitor(s) intending to help them find more sources containing these inhibitors. The application is trained to identify various sources rich in thirteen coronavirus-2 key inhibitors. The sources are currently just aliments, plants, and seeds and the identification is done by their names.

Repurposing antibiotics as potent multi-drug candidates for SARS-CoV-2 delta and omicron variants: molecular docking and dynamics.

There is a daunting public health emergency due to the emergence and rapid global spread of the new omicron variants of SARS-CoV-2. The variants differ in many characteristics, such as transmissibility, antigenicity and the immune system of the human hosts' shifting responses. This change in characteristics raises concern, as it leads to unknown consequences and also raises doubts about the efficacy of the currently available vaccines. As of March 2022, there are five variants of SARS-CoV-2 disseminating: the alpha, the beta, the gamma, the delta and the omicron variant. The omicron variant has more than 30 mutations on the spike protein, which is used by the virus to enter the host cell and is also used as a target for the vaccines. In this work, we studied the possible anti-COVID-19 effect of two molecules by molecular docking using Autodock Vina and molecular dynamic simulations using Gromacs 2020 software. We docked amoxicillin and clavulanate to the main protease (Mpro), the RNA-dependent RNA polymerase (RdRp) and the spike protein receptor-binding domain (SRBD) of the wild type with the two variants (delta and omicron) of SARS-CoV-2. The docking results show that the ligands bound tightly with the SRBD of the omicron variant, while the dynamic simulation revealed the ability of amoxicillin to bind to the SRBD of both variants' delta and omicron. The high number of mutations that occurred in both variants increases the affinity of amoxicillin towards them. Communicated by Ramaswamy H. Sarma.

Quinic and Digallic acids from Pistacia atlantica Desf. Leaves Extracts as Potent Dual Effect Inhibitors against main Protease and RNA-dependent RNA Polymerase of SARS-CoV-2.

BACKGROUND: Through this study, the Chemical composition realized by UHPLC-DADESI- MSn allowed the detection of different phenolic compound groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking. OBJECTIVE: The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects. METHODS: Chemical composition was realized by UHPLC-DAD-ESI-MSn, and the inhibition of the main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 was studied using molecular docking with Autodock Vina software. ADMET analysis was carried out. RESULTS: The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1µM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drug candidates. CONCLUSION: This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves are studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.

Exploring Structural Mechanism of COVID-19 Treatment with Glutathione as a Potential Peptide Inhibitor to the Main Protease: Molecular Dynamics Simulation and MM/PBSA Free Energy Calculations Study.

The 2019-novel coronavirus has unfolded everywhere in the world and obliged a billion human beings in open confinement, whereas many treatments, and vaccines have been proposed towards this pandemic. The main protease (Mpro) is an attractive drug target due to the fact that it is the essential protein for virus invasion. This research tests in silico the effect of five vitamins towards Mpro, by employing molecular docking (MD), molecular dynamics simulation (MDS) with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) studies. To achieve this work, we have applied some software's as Autodock Vina, Discovery Studio Visualizer, APBS, and GROMACS. The inhibitors used were decided entirely on the basis of their importance in the production of red blood cells that prevent anemia, in lymphocyte immune system responses, in the regulation of reactive oxygen species production, such as tocopherol (vitamin E), thiamine (vitamin B1), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), and glutathione (GSH). The best inhibitor pose established at the highest repetition ratio (RR) and the minimal affinity energy value (MEV), then the best selected inhibitor was considered to MDS. The results indicate that GSH is the leading inhibitor model among the other tested vitamins in the active site of Mpro with a RR value of 94% and MEV of - 5.5 kcal/mol, its RMSD, RMSF, Rg, and hydrogen bonds show stability with Mpro. Furthermore, thiamine, biotin, and tocopherol are viewed as satisfying inhibitors to Mpro, but pyridoxine was observed as the weakest inhibitor. Based on our result, we could recommend the usage of glutathione and vitamin B family as a supportive strategy for feasible remedy of COVID-19 virus.

Hispidin and Lepidine E: Two Natural Compounds and Folic Acid as Potential Inhibitors of 2019-novel Coronavirus Main Protease (2019- nCoVMpro), Molecular Docking and SAR Study.

BACKGROUND: 2019-nCoVis, a novel coronavirus was isolated and identified in 2019 in the city of Wuhan, China. On February 17, 2020 and according to the World Health Organization, 71, 429 confirmed cases worldwide were identified, among them 2162 new cases were recorded in the last 24 hours. One month later, the confirmed cases jumped to 179111, with 11525 new cases in the last 24 hours, with 7426 total deaths. No drug or vaccine is present at the moment for human and animal coronavirus. METHODS: The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) is known for involving in counteracting the host innate immune response. RESULTS: This work presents the inhibitory effect of some natural compounds against 3CL hydrolase enzyme, and explains the main interactions in inhibitor-enzyme complex. Molecular docking study was carried out using Autodock Vina. By screening several molecules, we identified three candidate agents that inhibit the main protease of coronavirus. Hispidin, lepidine E, and folic acid are bound tightly in the enzyme, therefore strong hydrogen bonds have been formed (1.69-1.80Å) with the active site residues. CONCLUSION: This study provides a possible therapeutic strategy for CoViD-19.