Combined molecular docking and dynamics simulations studies of natural compounds as potent inhibitors against SARS-CoV-2 main protease.

Main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2 the new strain of coronavirus. In this study, we evaluated biologically active compounds present in medicinal plants as potential SARS-CoV-2 Mpro inhibitors, using a molecular docking study with Autodock Vina software. Top seven compounds Afzelin, Phloroglucinol, Myricetin-3-O- rutinosid Tricin 7-neohesperidoside, Silybin, Kaempferol and Silychristin among 50 molecules of natural Origin (Algerian Medicinal plants) were selected which had better and significantly low binding energy as compared to the reference molecule with binding affinities of -9.3, -9.3, -9, -8.9, -8.5, 8.3 and -8.3 kcal mol-1 respectively. Then, we analyzed the ADME properties of the best 7 ligands using the Web server SwissADME. Two of small molecules have been shown to be the ideal candidates for further drug development. Finally, the stability of the both compounds complexed with Mpro was validated through molecular dynamics (MD) simulation, they displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations, moreover, Silybin could form more stable complex with Mpro than Silychristin.Communicated by Ramaswamy H. Sarma.

Cameroonian medicinal plants as potential candidates of SARS-CoV-2 inhibitors.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic instigated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which changed the daily train of the world's population and cause several dead. Despite the significant efforts made in developing vaccines and therapeutic drugs, there is currently no available effective treatment against this new coronavirus infection, hence the need to continue research which is aimed at limiting the progression of this virus. The present study which has as objective to carry out in silico studies on the metabolites of some Cameroonian medicinal plants of the Asteraceae family with a view to propose potential molecules to fight against COVID-19. The selected plants are commonly used to treat respiratory infectious diseases, and for this reason they may contain some constituents which could exhibit an antiviral activity against SARS-CoV-2. In this work, a set of 74 naturally occurring compounds are computed with SARS-CoV-2 main protease protein (PDB ID: 6lu7) and spike protein (PDB ID: 6m0j) for their affinity and stability using binding energy analysis and molecular docking. Chrysoeriol-7-O-ß-D-glucuronopyranoside (compound 16) has showed promising results including excellent Absorption, Distribution, Metabolism and Excretion (ADME) parameters as well as insignificant toxicity. Finally, the stability of this compound is complex with the two proteins validated through molecular dynamics (MD) simulation, they displayed stable trajectory and molecular properties with consistent interaction profile in molecular dynamics simulations. These findings call for further in vitro and in vivo challenges of phytoconstituents against the COVID-19 as a potential agent to fight the spread of this dramatic pandemic.Communicated by Ramaswamy H. Sarma.

In silico investigation of phytoconstituents from Cameroonian medicinal plants towards COVID-19 treatment.

In silico studies performed on the metabolites of four Cameroonian medicinal plants with a view to propose potential molecules to fight against COVID-19 were carried out. At first, molecular docking was performed for a set of 84 selected phytochemicals with SARS-CoV-2 main protease (PDB ID: 6lu7) protein. It was further followed by assessing the pharmacokinetics and pharmacological abilities of 15 compounds, which showed low binding energy values. As the screening criteria for their ADMET properties were performed, only two compounds have shown suitable pharmacological properties for human administration which were shortlisted. Furthermore, the stability of binding of these compounds was assessed by performing molecular dynamics (MD) simulations. Based on further analysis through molecular dynamics simulations and reactivity studies, it was concluded that only the Pycnanthuquinone C (17) and the Pycnanthuquinone A (18) extracted from the Pycnanthus angolensis could be considered as candidate inhibitors for targeted protein. Indeed, we expect that these compounds could show excellent in vitro and in vivo activity against SARS-CoV-2. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01939-7.

Unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitors: Molecular docking, molecular dynamics, and ADME scoring investigations.

COVID-19 pandemic caused by very severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) agent is an ongoing major global health concern. The disease has caused more than 452 million affected cases and more than 6 million death worldwide. Hence, there is an urgency to search for possible medications and drug treatments. There are no approved drugs available to treat COVID-19 yet, although several vaccine candidates are already available and some of them are listed for emergency use by the world health organization (WHO). Identifying a potential drug candidate may make a significant contribution to control the expansion of COVID-19. The in vitro biological activity of asymmetric disulfides against coronavirus through the inhibition of SARS-CoV-2 main protease (Mpro) protein was reported. Due to the lack of convincing evidence those asymmetric disulfides have favorable pharmacological properties for the clinical treatment of Coronavirus, in silico evaluation should be performed to assess the potential of these compounds to inhibit the SARS-CoV-2 Mpro. In this context, we report herein the molecular docking for a series of 40 unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitor. The optimal binding features of disulfides within the binding pocket of SARS-CoV-2 endoribonuclease protein (Protein Data Bank [PDB]: 6LU7) was described. Studied compounds were ranked for potential effectiveness, and those have shown high molecular docking scores were proposed as novel drug candidates against SARS-CoV-2. Moreover, the outcomes of drug similarity and ADME (Absorption, Distribution, Metabolism, and Excretion) analyses have may have the effectiveness of acting as medicines, and would be of interest as promising starting point for designing compounds against SARS-CoV-2. Finally, the stability of these three compounds in the complex with Mpro was validated through molecular dynamics (MD) simulation, in which they displayed stable trajectory and molecular properties with a consistent interaction profile.

Combined docking methods and molecular dynamics to identify effective antiviral 2, 5-diaminobenzophenonederivatives against SARS-CoV-2.

The aim of this work is to contribute to the research in finding lead compounds for clinical use, to identify new drugs that target the SARS-CoV-2 virus main protease (Mpro). In this study, we used molecular docking strategies to analyze 2.5-diaminobenzophenone compounds against Malaria and to compare results with the Nelfinavir as a FDA-approved HIV-1 protease inhibitor recommended for the treatment of COVID-19. These efforts identified the potential compounds against SAR-COV-2 Mpro with the docking scores ranges from -6.1 to -7.75 kcal/mol, which exhibited better interactions than the Nelfinavir. Among thirty-six studied, compounds 20c, 24c, 30c, 34c, 35c and 36c showed the highest affinity and involved in forming hydrophobic interactions with Glu166, Thr24, Thr25, and Thr26 residues and forming H-bonding interactions with Gln189, Cys145, and His41residues. Pharmacokinetic properties and toxicity (ADMET) were also determined for identified compounds. This study result in the identification of two compounds 35 and 36 having high binding affinity, good pharmacokinetics properties and lowest toxicity. The structural stability and dynamics of lead compounds within the active site of 3CLpro was also examined using molecular dynamics (MD) simulation. Essential dynamics demonstrated that the two complexes remain stable during the entire duration of simulation. We have shown that these two lead molecules would have the potential to act as promising drug-candidates and would be of interest as starting point for designing compounds against the SARS-CoV-2.