key: cord-0823645-azvq8xr6 authors: Abosheasha, Mohammed A.; El‐Gowily, Afnan H. title: Superiority of cilostazol among antiplatelet FDA‐approved drugs against COVID 19 M(pro) and spike protein: Drug repurposing approach date: 2020-09-27 journal: Drug Dev Res DOI: 10.1002/ddr.21743 sha: d5074098b99751b32b4e7618cccc19d897f16a8f doc_id: 823645 cord_uid: azvq8xr6 Coronavirus disease 2019 (COVID 19) was first identified in Wuhan, China near the end of 2019. To date, COVID‐19 had spread to almost 235 countries and territories due to its highly infectious nature. Moreover, there is no vaccine or Food and Drug Administration (FDA)‐approved drug. More time is needed to establish one of them. Consequently, the drug repurposing approach seems to be the most attractive and quick solution to accommodate this crisis. In this regard, we performed molecular docking‐based virtual screening of antiplatelet FDA‐approved drugs on the key two viral target proteins: main protease (M(pro)) and spike glycoprotein (S) as potential inhibitor candidates for COVID‐19. In the present study, 15 antiplatelet FDA‐approved drugs were investigated against the concerned targets using the Molecular Docking Server. Our study revealed that only cilostazol has the most favorable binding interaction on M(pro) (PDB ID: 6LU7) and cilostazol, iloprost, epoprostenol, prasugrel, and icosapent ethyl have a higher binding affinity on spike glycoprotein (S) (PDB ID: 6VYB) compared with recent anti‐CoVID‐19. Therefore, cilostazol is a promising FDA drug against COVID‐19 by inhibiting both M(pro) and S protein. The insights gained in this study may be useful for quick approach against COVID‐19 in the future. of genomic genome RNA and nucleocapsid protein (N), which is embedded inside phospholipid bilayers and is protected by two separate forms of spike proteins: spike glycoprotein trimmer (S) in all CoVs, and the hemagglutinin-esterase HE in some CoVs. The membrane protein (M) (transmembrane glycoprotein type III) and the envelope protein (E) are positioned among the S proteins in the viral envelope. CoVs were named based on the crown-shaped appearance . The estimated structure of SARS-CoV-2 is shown in Figure 1 . SARS-CoV-2 causes severe respiratory tract infection in humans utilizing angiotensin-converting enzyme 2 (ACE2) receptors as a gate to infect epithelial cells of the lungs by attachment of spike glycoprotein (S) (Chen, Guo, Pan, & Zhao, 2020) . The genomic sequence of SARS-CoV-2 was isolated and obtained by Lu et al. (2020) also the crystal structure of COVID-19 main protease (M pro ) was confirmed by Jin et al. that considered as a potential drug target protein for inhibition of SARS-CoV-2 replication. The M pro is a key protein in preventing virus maturation (Jin et al., 2020) . Hence, targeting nonstructural (M pro ) and structural (S) proteins has a promising approach for effective treatment against SARS-CoV-2 (Sohag et al., 2020) . Scientists investigate alternative therapies for COVID-19 using artificial intelligence for identification of possible candidates. Many researchers working in the field of drug repurposing use Drug bank and molecular docking software to hopefully find potential treatment. Drug repurposing (also commonly named as drug repositioning) is a drug development strategy used to identify novel uses for existing approved and investigational drugs outside of their original indication. In comparison to conventional pipelines for drug production, this approach has many advantages. Unlike conventional drug production, which could be ineffective in preclinical and early stage clinical trials based on safety issues, this risk is mitigated by the use of drugs that have demonstrated safety records in previous studies. Accordingly, drug repurposing is also significantly more efficient and cost-effective than traditional drug development since preclinical and early stage clinical trials do not need to be repeated (Pushpakom et al., 2018) . In past respiratory virus pandemics, such as H1N1 influenza, therapeutical anticoagulants have been used (Obi et al., 2019) . A recent study suggests that the use of heparin as a prophylactic agent in 99 patients has been associated with an improvement in mortality in a cohort study of 449 COVID-19 patients from Wuhan, China. However, the rate of prophylactic anticoagulants was low, further prospective studies are needed to confirm this hypothesis (Tremblay et al., 2020) . Also, Xijing Hospital started the clinical trial proposing the early usage of aspirin is expected to reduce the incidence of severe and critical COVID-19 patients, minimize their hospital staying, and avoid the occurrence of cardiovascular complications based on aspirin role as antivirus replication, antiplatelet aggregation, antiinfection, and antilung injury (NCT04365309, 2020); which raises the question of whether the antiplatelets may play a role in the treatment of COVID-19. To answer this question, we performed molecular docking-based virtual screening of antiplatelet Food and Drug Administration (FDA)approved drugs on the following two viral target proteins: main protease (M pro ) and spike glycoprotein (S) as potential inhibitor candidates for COVID-19. The computational investigations were performed using the Molecular Docking Server (Bikadi & Hazai, 2009 ) (https://www.dockingserver. com) based on AutoDock 4 for docking calculation. In cases where protein and ligand partial charges were calculated with the PM6 method using MOPAC2009 software (Huey, Morris, Olson, & Goodsell, 2007; Stewart, 2009) . Docking simulations were performed using the Lamarckian genetic algorithm (LGA) and the Solis and Wets local search method (Solis & Wets, 1981) . Initial position, orientation, and torsions of the ligand molecules were set randomly. Each docking experiment was derived from 100 different runs that were set to terminate after a maximum of 2,500,000 energy evaluations. In the current study, the parameters of estimated free energy of binding, inhibition constant (K i ), total estimated energy of vdW + Hbond + desolv (EVHD), electrostatic energy, total intermolecular energy, frequency of binding, and interacting surface area were evaluated to estimate the favorable binding of antiplatelet FDA-approved drugs against COVID-19 (M pro ) and spike glycoprotein (S). (Table 4) . On the other hand, other investigated antiplatelet FDA-approved drugs like: clopidogrel, ticagrelor, ticlopidine, anagrelide, and vorapaxar showed better binding affinity with an estimated free energy of binding −7.77, −7.77, −7.74, −7.31, and −7.10 kcal/mol, respectively, than umifenovir, hydroxychloroquine, and darunavir with an estimated free energy of binding −6.98, −6.61, and −6.01 kcal/mol, respectively (Table 4) . In the past few months, COVID-19's rapidly spread outbreak has raised challenges to the global health market. To date, there is no effective vaccine or approved medication to treat this disease. Given the time needed to establish one of these alternatives, the drug repurposing approach appears to be the most attractive and quick. To The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. The authors declare no conflicts of interest regarding financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) this work. No work was done on animals and/or humans. Mohammed A. Abosheasha https://orcid.org/0000-0002-8866- Afnan H. 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