Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals.

Male infertility is significantly influenced by the plasma-protein sex hormone-binding globulin (SHBG). Male infertility, erectile dysfunction, prostate cancer, and several other male reproductive system diseases are all caused by reduced testosterone bioavailability due to its binding to SHBG. In this study, we have identified 345 phytochemicals from 200 literature reviews that potentially inhibit severe acute respiratory syndrome coronavirus 2. Only a few studies have been done using the SARS-CoV-2 inhibitors to identify the SHBG inhibitor, which is thought to be the main protein responsible for male infertility. In virtual-screening and molecular-docking experiments, cryptomisrine, dorsilurin E, and isoiguesterin were identified as potential SHBG inhibitors with binding affinities of -9.2, -9.0, and -8.8 kcal/mol, respectively. They were also found to have higher binding affinities than the control drug anastrozole (-7.0 kcal/mol). In addition to favorable pharmacological properties, these top three phytochemicals showed no adverse effects in pharmacokinetic evaluations. Several molecular dynamics simulation profiles' root-mean-square deviation, radius of gyration, root-mean-square fluctuation, hydrogen bonds, and solvent-accessible surface area supported the top three protein-ligand complexes' better firmness and stability than the control drug throughout the 100 ns simulation period. These combinatorial drug-design approaches indicate that these three phytochemicals could be developed as potential drugs to treat male infertility.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Dietary polyphenols mitigate SARS-CoV-2 main protease (Mpro)-Molecular dynamics, molecular mechanics, and density functional theory investigations.

The recent evolution of the SARS-like Coronavirus has ravaged the world. The deadly virus has claimed over millions of lives across the world and hence highlights the need to develop effective therapeutic drugs to contain the disease posed by this parasite. In this study, the inhibitory potential of fifty (50) dietary polyphenols against Coronavirus (SARS-CoV-2) main protease (Mpro) was conducted using the Autodock Vina Molecular docking tool. In the virtual screening process, the binding affinity of Remdesivir (-7.7 kcal/mol) currently used to treat COVID-19 patients was set as the cut-off value to screen out less probable inhibitors. Ellagic acid, Kievitone, and Punicalin were the only promising ligands with binding affinities (-8.9 kcal/mol, -8.0 kcal/mol and -7.9 kcal/mol respectively) lower than the set cut-off value. Furthermore, we validated Ellagic acid and Kievitone efficacy by subjecting them to molecular dynamics simulation and further stability was assessed at the molecular mechanics and quantum levels. The overall analysis indicates both compounds demonstrate higher stability and inhibitory potential to bind to the crucial His41 and Cys145 catalytic dyad of Mpro than the standard drug. However, further analysis of punicalin after evaluating its docking score was not conducted as the ligand pharmacokinetics properties suggests it could pose serious adverse effect to the health of participants in clinical trials. Hence, we employed a more safe approach by filtering out the compound during this study. Conclusively, while Ellagic acid and kievitone polyphenolic compounds have been demonstrated to be promising under this in silico research, further studies are needed to substantiate their clinical relevance.

Computational screening of phytochemicals from three medicinal plants as inhibitors of transmembrane protease serine 2 implicated in SARS-CoV-2 infection.

Background: SARS-CoV-2 infection or COVID-19 is a major global public health issue that requires urgent attention in terms of drug development. Transmembrane Protease Serine 2 (TMPRSS2) is a good drug target against SARS-CoV-2 because of the role it plays during the viral entry into the cell. Virtual screening of phytochemicals as potential inhibitors of TMPRSS2 can lead to the discovery of drug candidates for the treatment of COVID-19. Purpose: The study was designed to screen 132 phytochemicals from three medicinal plants traditionally used as antivirals; Zingiber officinalis Roscoe (Zingiberaceae), Artemisia annua L. (Asteraceae), and Moringa oleifera Lam. (Moringaceae), as potential inhibitors of TMPRSS2 for the purpose of finding therapeutic options to treat COVID-19. Methods: Homology model of TMPRSS2 was built using the ProMod3 3.1.1 program of the SWISS-MODEL. Binding affinities and interaction between compounds and TMPRSS2 model was examined using molecular docking and molecular dynamics simulation. The drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of potential inhibitors of TMPRSS2 were also assessed using admetSAR web tool. Results: Three compounds, namely, niazirin, quercetin, and moringyne from M. oleifera demonstrated better molecular interactions with binding affinities ranging from -7.1 to -8.0 kcal/mol compared to -7.0 kcal/mol obtained for camostat mesylate (a known TMPRSS2 inhibitor), which served as a control. All the three compounds exhibited good drug-like properties by not violating the Lipinski rule of 5. Niazirin and moringyne possessed good ADMET properties and were stable in their interactions with the TMPRSS2 based on the molecular dynamics simulation. However, the ADMET tool predicted the potential hepatotoxic and mutagenic effects of quercetin. Conclusion: This study demonstrated the potentials of niazirin, quercetin, and moringyne from M. oleifera, to inhibit the activities of human TMPRSS2, thus probably being good candidates for further development as new drugs for the treatment or management of COVID-19.

In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis.

Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2-22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.

Phytoconstituents from ten natural herbs as potent inhibitors of main protease enzyme of SARS-COV-2: In silico study.

Background: Lack of treatment of novel Coronavirus disease led to the search of specific antivirals that are capable to inhibit the replication of the virus. The plant kingdom has demonstrated to be an important source of new molecules with antiviral potential. Purpose: The present study aims to utilize various computational tools to identify the most eligible drug candidate that have capabilities to halt the replication of SARS-COV-2 virus by inhibiting Main protease (Mpro) enzyme. Methods: We have selected plants whose extracts have inhibitory potential against previously discovered coronaviruses. Their phytoconstituents were surveyed and a library of 100 molecules was prepared. Then, computational tools such as molecular docking, ADMET and molecular dynamic simulations were utilized to screen the compounds and evaluate them against Mpro enzyme. Results: All the phytoconstituents showed good binding affinities towards Mpro enzyme. Among them laurolitsine possesses the highest binding affinity i.e. -294.1533 kcal/mol. On ADMET analysis of best three ligands were simulated for 1.2 ns, then the stable ligand among them was further simulated for 20 ns. Results revealed that no conformational changes were observed in the laurolitsine w.r.t. protein residues and low RMSD value suggested that the Laurolitsine-protein complex was stable for 20 ns. Conclusion: Laurolitsine, an active constituent of roots of Lindera aggregata, was found to be having good ADMET profile and have capabilities to halt the activity of the enzyme. Therefore, this makes laurolitsine a good drug candidate for the treatment of COVID-19.

In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis.

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.

Structure features of peptide-type SARS-CoV main protease inhibitors: Quantitative structure activity relationship study.

In the present work, an extensive QSAR (Quantitative Structure Activity Relationships) analysis of a series of peptide-type SARS-CoV main protease (MPro) inhibitors following the OECD guidelines has been accomplished. The analysis was aimed to identify salient and concealed structural features that govern the MPro inhibitory activity of peptide-type compounds. The QSAR analysis is based on a dataset of sixty-two peptide-type compounds which resulted in the generation of statistically robust and highly predictive multiple models. All the developed models were validated extensively and satisfy the threshold values for many statistical parameters (for e.g. R2 â€‹= â€‹0.80-0.82, Q2 loo â€‹= â€‹0.74-0.77, Q 2 LMO  â€‹= â€‹0.66-0.67). The developed QSAR models identified number of sp2 hybridized Oxygen atoms within seven bonds from aromatic Carbon atoms, the presence of Carbon and Nitrogen atoms at a topological distance of 3 and other interrelations of atom pairs as important pharmacophoric features. Hence, the present QSAR models have a good balance of Qualitative (Descriptive QSARs) and Quantitative (Predictive QSARs) approaches, therefore useful for future modifications of peptide-type compounds for anti- SARS-CoV activity.