2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease.
ABSTRACT: The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 Mpro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 Mpro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants (Ki values) for each 2-pyridone-containing compound with SARS-CoV-2 Mpro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 Mpro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 Mpro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki values <1 ?M. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 Mpro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.
Project description:The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the M<sup>pro</sup> and PL<sup>pro</sup> enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.
Project description:COVID-19 has become a global pandemic and there is an urgent call for developing drugs against the virus (SARS-CoV-2). The 3C-like protease (3CL<sup>pro</sup>) of SARS-CoV-2 is a preferred target for broad spectrum anti-coronavirus drug discovery. We studied the anti-SARS-CoV-2 activity of <i>S. baicalensis</i> and its ingredients. We found that the ethanol extract of <i>S. baicalensis</i> and its major component, baicalein, inhibit SARS-CoV-2 3CL<sup>pro</sup> activity <i>in vitro</i> with IC<sub>50</sub>'s of 8.52 µg/ml and 0.39 µM, respectively. Both of them inhibit the replication of SARS-CoV-2 in Vero cells with EC<sub>50</sub>'s of 0.74 µg/ml and 2.9 µM, respectively. While baicalein is mainly active at the viral post-entry stage, the ethanol extract also inhibits viral entry. We further identified four baicalein analogues from other herbs that inhibit SARS-CoV-2 3CL<sup>pro</sup> activity at µM concentration. All the active compounds and the <i>S. baicalensis</i> extract also inhibit the SARS-CoV 3CL<sup>pro</sup>, demonstrating their potential as broad-spectrum anti-coronavirus drugs.
Project description:Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (M<sup>pro</sup> or 3CL<sup>pro</sup>) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the M<sup>pro</sup> of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 M<sup>pro</sup>. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 M<sup>pro</sup>. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 M<sup>pro</sup>. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of M<sup>pro</sup> with ZINC02123811. MD simulation results indicated that M<sup>pro</sup> with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 M<sup>pro</sup> to address COVID-19.
Project description:Traditional medicines contain natural products (NPs) as main ingredient which always give new direction and paths to develop new advanced medicines. In the COVID-19 pandemic, NPs can be used or can help to find new compound against it. The SARS coronavirus-2 main protease (SARS CoV-2 M<sup>pro</sup>) enzyme, arbitrate viral replication and transcription, is target here. The study show that, from the electronic features and binding affinity of all the NPs with the enzyme, the compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor. More than fifty NPs were screened for the target and one terpenoid (T3) from marine sponge <i>Cacospongia mycofijiensis</i> shows excellent SARS CoV-2 M<sup>pro</sup> inhibitory activity in comparison with known peptide based inhibitors. The molecular dynamics simulation studies of the terpenoids with the protein indicates that the complex is stable and hydrogen bonds are involved during the complexation. Considering binding affinity, bioavailability, pharmacokinetics and toxicity of the compounds, it is proposed that the NP T3 can act as a potential drug candidate against COVID-19 virus.
Project description:Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (M<sup>pro</sup>) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from <i>Echinacea-angustifolia</i>, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 M<sup>pro</sup>. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 M<sup>pro</sup> catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 M<sup>pro</sup> with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from <i>Echinacea angustifolia</i> for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 M<sup>pro</sup> antagonist with higher affinity and drug-likeness.
Project description:The outbreak of a new coronavirus (SARS-CoV-2), which is responsible for the COVID-19 disease and is spreading rapidly around the world, urgently requires effective therapeutic treatments. In this context, drug repurposing represents a valuable strategy, as it enables accelerating the identification of drug candidates with already known safety profiles, possibly aiding in the late stages of clinical evaluation. Moreover, therapeutic treatments based on drugs with beneficial multi-target activities (polypharmacology) may show an increased antiviral activity or help to counteract severe complications concurrently affecting COVID-19 patients. In this study, we present the results of a computational drug repurposing campaign that aimed at identifying potential inhibitors of the main protease (M<sup>pro</sup>) of the SARS-CoV-2. The performed <i>in silico</i> screening allowed the identification of 22 candidates with putative SARS-CoV-2 M<sup>pro</sup> inhibitory activity. Interestingly, some of the identified compounds have recently entered clinical trials for COVID-19 treatment, albeit not being assayed for their SARS-CoV-2 antiviral activity. Some candidates present a polypharmacology profile that may be beneficial for COVID-19 treatment and, to the best of our knowledge, have never been considered in clinical trials. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.
Project description:The novel SARS-CoV-2 is the etiological agent causing the Coronavirus disease 2019 (COVID-19), which continues to become an inevitable pandemic outbreak. Over a short span of time, the structures of therapeutic target proteins for SARS-CoV-2 were identified based on the homology modelled structure of similar SARS-CoV transmission of 2003. Since the onset of the disease, the research community has been looking for a potential drug lead. Out of all the known resolved structures related to SARS-CoV, Main protease (M<sup>pro</sup>) is considered an attractive anti-viral drug target on the grounds of its role in viral replication and probable non-interactive competency to bind to any viral host protein. To the best of our knowledge, till date only one compound has been identified and tested in-vivo as a potent inhibitor of M<sup>pro</sup> protein, addressed as N3 (PubChem Compound CID: 6323191) and is known to bind irreversibly to M<sup>pro</sup> suppressing its activity. Using computational approach, we intend to identify a probable natural fungal metabolite to interact and inhibit M<sup>pro</sup>. After screening various small molecules for molecular docking and dynamics simulation, we propose Pyranonigrin A, a secondary fungal metabolite to possess potent inhibitory potential against the Main protease (M<sup>pro</sup>) expressed in SARS-CoV-2 virus.
Project description:The coronavirus disease infections (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) have been emerging in the entire world. Therefore, it is necessary to find out potential therapeutic pharmaceuticals for this disease. This study investigates the inhibitory effect of the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) using pharmaceuticals containing ?-ketoamide group and pyridone ring based on molecular docking. Of these, eight pharmaceuticals approved by US-Food and Drug Administration have shown good contact with the catalytic residues of 3CLpro. They are telaprevir, temsirolimus, pimecrolimus, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide. Their binding affinity score ranged from -5.6 to -7.4 kcal/mol. Hydrogen bonds were observed and reported. To the knowledge, this study report for the first time a compound that could be binding to ALA285, the new residue resulting from genetic modification of 3CLpro of SARS-CoV-2 that has increased its catalytic activity 3.6-fold compared with its predecessor 3CLpro of SARS-CoV. It is recommended that telaprevir, and pyridone-containing pharmaceuticals including aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide be repurposed for COVID-19 treatment after suitable validation and clinical trials.
Project description:This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (M<sup>pro</sup>) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the M<sup>pro</sup> active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV M<sup>pro</sup> and the highly homologous SARS-CoV-2 M<sup>pro</sup>. The supporting information (supplementary material) provides an illustrated step-by-step guide for the inhibitor design, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 M<sup>pro</sup>.
Project description:Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral outbreak started in late 2019 and rapidly became a serious health threat to the global population. COVID-19 was declared a pandemic by the World Health Organization in March 2020. Several therapeutic options have been adopted to prevent the spread of the virus. Although vaccines have been developed, antivirals are still needed to combat the infection of this virus. SARS-CoV-2 is an enveloped virus, and its genome encodes polyproteins that can be processed into structural and nonstructural proteins. Maturation of viral proteins requires cleavages by proteases. Therefore, the main protease (3 chymotrypsin-like protease (3CL<sup>pro</sup>) or M<sup>pro</sup>) encoded by the viral genome is an attractive drug target because it plays an important role in cleaving viral polyproteins into functional proteins. Inhibiting this enzyme is an efficient strategy to block viral replication. Structural studies provide valuable insight into the function of this protease and structural basis for rational inhibitor design. In this review, we describe structural studies on the main protease of SARS-CoV-2. The strategies applied in developing inhibitors of the main protease of SARS-CoV-2 and currently available protein inhibitors are summarized. Due to the availability of high-resolution structures, structure-guided drug design will play an important role in developing antivirals. The availability of high-resolution structures, potent peptidic inhibitors, and diverse compound scaffolds indicate the feasibility of developing potent protease inhibitors as antivirals for COVID-19.