In silico Study of Pharmacological Treatments against SARS-CoV2 Main Protease (original) (raw)
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International Journal of pharma and Bio Sciences, 2021
The COVID-19 pandemic triggered by SARS-CoV-2 is a worldwide health disaster. Main protease is an attractive drug target among coronaviruses, due to its vital role in processing the polyproteins that are translated from the viral RNA. There is presently no exact drug or treatment for this disease caused by SARS-CoV-2.Speeding up drug innovation is immediately required. In the present study, we report the potential inhibitory activity of some FDA approved drugs against SARS-CoV-2 main protease by molecular docking study to investigate their binding affinity in protease active sites. Total 47 FDA approved drugs were selected for molecular docking with main COVID-19 protease. The docking of selected drugs to the active site of protein was performed using AutoDock software. Docking was achieved to attain a population of potential conformations and alignments for the ligand at the binding site. Docking study revealed that great inhibitory efficacy of the one anti-H1N1 drug (Oseltamivir), one anti-TB drug (Rifampin), four anti-HIV drugs (Maraviroc, Etravirine, Indinavir, Rilpivirine) and seven antimalarial drugs (Atovaquone, Quinidine, Halofantrine, Amodiaquine, Tetracylcine, Azithromycin, hydroxycholoroquine) was found since they could launch H2 bonds with different amino acid residues that caused an inhibition of SARS-CoV-2 protease activity with higher binding affinity ranging from (-10.67 to-8.3 kcal/mol). However, the in-silico abilities of the drug molecules tested in this study, further needs to be validated by carrying out in vitro and in vivo studies. Moreover, this study spreads the potential use of current drugs to be considered and used to comprise the fast expanding SARS-CoV-2 infection.
Research Square (Research Square), 2020
The pandemic due to the novel coronavirus 2019, SARS-CoV-2, has led to a global health and economic crisis. The disease, named coronavirus disease (COVID-19), has already affected 3090445 and killed over 217769 people worldwide, as of April 30, 2020. So far, there is no speci c effective medicine or vaccine against SARS-CoV-2. Several existing and approved drugs are under clinical studies for re-purposing. However, owing to the emergent situation and thereby to avoid time needed for de novo drug discovery, drug re-purposing remains to be the best option to nd an effective therapeutic against the virus. Thus, the preset study was designed to evaluate potency of 82 compound/drugs in inhibiting the main protease (3CLPro) of SARS-CoV-2, using molecular docking tool. This protease is a vital enzyme for replication of the virus, and is thus a promising drug target. The analyzed compounds include 16 known protease inhibitors, two recently suggested α-ketoamides, 24 recently reported putative inhibitors, and 40 phytochemicals. The results indicate that Ritonavir, Indinavir, Montelukast, Nel navir, Candoxatril, Tigecycline and Lopinavir to be very potent protease inhibitors. Further, several other drugs and compounds, including phytochemicals, have been identi ed / predicted to be potent in inhibiting the enzyme. In addition, we hereby report relative e cacies of these compounds in inhibiting 3CLPro. Thus, the present study is signi cant in the therapeutic intervention of COVID-19.
Potential protease inhibitors and their combinations to block SARS-CoV-2
Journal of Biomolecular Structure and Dynamics
COVID-19, which has emerged recently as a pandemic viral infection caused by SARS-coronavirus 2 has spread rapidly around the world, creating a public health emergency. The current situation demands an effective therapeutic strategy to control the disease using drugs that are approved, or by inventing new ones. The present study examines the possible repurposing of existing anti-viral protease inhibitor drugs. For this, the structural features of the viral spike protein, the substrate for host cell protease and main protease of the available SARS CoV-2 isolates were established by comparing with related viruses for which antiviral drugs are effective. The results showed 97% sequence similarity among SARS and SARS-CoV-2 main protease and has same cleavage site positions and ACE2 receptor binding region as in the SARS-CoV spike protein. Though both are N-glycosylated, unlike SARS-CoV, human SARS-CoV-2 S-protein was O-glycosylated as well. Molecular docking studies were done to explore the role of FDA approved protease inhibitors to control SARS-CoV-2 replication. The results indicated that, Ritonavir has the highest potency to block SARS-CoV-2 main protease and human TMPRSS2, a host cell factor that aids viral infection. Other drugs such as Indinavir and Atazanavir also showed favourable binding with Cathepsin B/L that helped viral fusion with the host cell membrane. Further molecular dynamics simulation and MM-PBSA binding free energy calculations confirmed the stability of protein-drug complexes. These results suggest that protease inhibitors particularly Ritonavir, either alone or in combination with other drugs such as Atazanavir, have the potential to treat COVID 19.
Computational Determination of Potential Inhibitors of SARS-CoV2 Main Protease
The novel coronavirus (SARS-CoV-2) has infected several million people and caused thousands of deaths worldwide since December 2019. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. Therefore, in this context, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro, and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a database of ∼4600 natural compounds, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including three natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit a large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals interaction. We also found that Glu166 forms H-bonds to all of the inhibitors. Replacing Glu166 by an alanine residue leads to ∼2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potential drugs inhibiting SARS-CoV-2. ■ INTRODUCTION Members of the Coronaviridae virus family often cause mild respiratory syndrome in humans. 1 However, the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) are transfected from animals to humans and cause severe cases of respiratory syndromes and deaths. 2,3 In 2002, SARS-CoV was first recorded in Guandong, China, and linked to 8096 laboratory-confirmed cases of infection and 774 deaths. 3 The natural reservoir of SARS-CoV is Chinese horseshoe bats, 4 and intermediate hosts are civet cats and raccoon dogs. 5 This shows that Coronavirus can induce severe symptoms and potential pneumonia and death. In December 2019, a novel coronavirus (2019-nCoV or SARS-CoV-2) that has a similar sequence to SARS-CoV emerged in Wuhan, Hubei province, China. 6−8 The initial cluster of infection seemed to relate to Huanan seafood market. SARS-CoV-2 is thought to originate from bat. though the intermediate hosts are still unknown; 9 human-to-human transmission has been validated. 10 As of May 7, 2020, SARS-CoV-2 has infected more than 3,800,000 people and caused over 265,000 deaths worldwide. 11 Coronaviruses have the largest genomes among all known RNA viruses, ranging from 26 to 32 kb in length, which encode structural and nonstructural proteins. 12,13 The SARS-CoV-2 genome encodes more than 20 proteins, which include the main protease (Mpro), a 3C-like protease (3CLP) that shares 96,1% similarity with 3CLP of SARS-CoV. 13,14 Mpro, a homodimeric cysteine protease, plays an important role in SARS virus replication and transcription. When the mRNA of the virus is translated polyproteins, Mpro is first autocleaved to become a mature enzyme, which in turn cleaves all of the 11 remaining downstream nonstructural proteins of the polyproteins to polypeptides, which are required for the replication process of the virus. 13 SARS-CoV-2 Mpro has thus been an attractive drug target. 14,15 Darunavir and ritonavir can potentially inhibit SARS-CoV-2 Mpro and have been put into clinical trials for COVID-19 treatment. 16,17
Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease
Frontiers in Chemistry
The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based an...
Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV2
A consensus virtual screening protocol has been applied to ca. 2000 approved drugs to seek inhibitors of the main protease (M pro) of SARS-CoV-2, the virus responsible for COVID-19. 42 drugs emerged as top candidates, and after visual analyses of the predicted structures of their complexes with M pro , 17 were chosen for evaluation in a kinetic assay for M pro inhibition. Remarkably 14 of the compounds at 100-μM concentration were found to reduce the enzymatic activity and 5 provided IC 50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4 μM), lercanidipine (16.2 μM), bedaquiline (18.7 μM), and efonidipine (38.5 μM). Structural analyses reveal a common cloverleaf pattern for the binding of the active compounds to the P1, P1′, and P2 pockets of M pro. Further study of the most active compounds in the context of COVID-19 therapy is warranted, while all of the active compounds may provide a foundation for lead optimization to deliver valuable chemotherapeutics to combat the pandemic.
article, 2020
The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.
2020
Due to the migratory flow of infected people with severe acute respiratory syndrome virus (SARS-CoV-2), the numbers of confirmed cases of coronavirus 2019 (COVID-19) infections is accelerating worldwide and pre-clinical evidence of antiviral agents that can combat this pandemic is still elusive. We identified published SAR-CoV efficacy experiments in which some selected compounds were used to test the reduction of the virus load in mice. We then developed a combined model based on scoping review, meta-analyses, and molecular docking studies to evaluate the effect size of preclinical studies of compounds that have been tested against SARS-CoV. Molecular docking studies of the inhibitors in the active pocket of COVID-19 protease were also performed. Our results identified three SARS-CoV inhibitors i.e. EIDD-2801, GS-5734 and amodiaquine that are excellent options for optimization and drug development to treat or cure COVID-19.
International Journal of Molecular Sciences, 2021
In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC50) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC50 inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC50) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and ...