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.

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations.

The main (Mpro) and papain-like (PLpro) proteases are highly conserved viral proteins essential for replication of the COVID-19 virus, SARS-COV-2. Therefore, a logical plan for producing new drugs against this pathogen is to discover inhibitors of these enzymes. Accordingly, the goal of the present work was to devise a computational approach to design, characterize, and select compounds predicted to be potent dual inhibitors - effective against both Mpro and PLpro. The first step employed LigDream, an artificial neural network, to create a virtual ligand library. Ligands with computed ADMET profiles indicating drug-like properties and low mammalian toxicity were selected for further study. Initial docking of these ligands into the active sites of Mpro and PLpro was done with GOLD, and the highest-scoring ligands were redocked with AutoDock Vina to determine binding free energies (ΔG). Compounds 89-00, 89-07, 89-32, and 89-38 exhibited favorable ΔG values for Mpro (-7.6 to -8.7 kcal/mol) and PLpro (-9.1 to -9.7 kcal/mol). Global docking of selected compounds with the Mpro dimer identified prospective allosteric inhibitors 89-00, 89-27, and 89-40 (ΔG -8.2 to -8.9 kcal/mol). Molecular dynamics simulations performed on Mpro and PLpro active site complexes with the four top-scoring ligands from Vina demonstrated that the most stable complexes were formed with compounds 89-32 and 89-38. Overall, the present computational strategy generated new compounds with predicted drug-like characteristics, low mammalian toxicity, and high inhibitory potencies against both target proteases to form stable complexes. Further preclinical studies will be required to validate the in silico findings before the lead compounds could be considered for clinical trials.

Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal.

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody-drug conjugates.

Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies.

Recently, the novel life-threatening coronavirus infection (COVID-19) was reported at the end of 2019 in Wuhan, China, and spread throughout the world in little time. The effective antiviral activities of natural products have been proved in different studies. In this review, regarding the effective herbal treatments on other coronavirus infections, promising natural products for COVID-19 treatment are suggested. An extensive search in Google Scholar, Science Direct, PubMed, ISI, and Scopus was done with search words include coronavirus, COVID-19, SARS, MERS, natural product, herb, plant, and extract. The consumption of herbal medicine such as Allium sativum, Camellia sinensis, Zingiber officinale, Nigella sativa, Echinacea spp. Hypericum perforatum, and Glycyrrhiza glabra, Scutellaria baicalensis can improve the immune response. It seems that different types of terpenoids have promising effects in viral replication inhibition and could be introduced for future studies. Additionally, some alkaloid structures such as homoharringtonine, lycorine, and emetine have strong anti-coronavirus effects. Natural products can inhibit different coronavirus targets such as S protein (emodin, baicalin) and viral enzymes replication such as 3CLpro (Iguesterin), PLpro (Cryptotanshinone), helicase (Silvestrol), and RdRp (Sotetsuflavone). Based on previous studies, natural products can be introduced as preventive and therapeutic agents in the fight against coronavirus.