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Identification of SGLT2 Inhibitor Ertugliflozin As a Treatment

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Identification of SGLT2 Inhibitor Ertugliflozin As a Treatment bioRxiv preprint doi: https://doi.org/10.1101/2021.06.18.448921; this version posted June 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Identification of SGLT2 inhibitor Ertugliflozin as a treatment for COVID-19 using computational and experimental paradigm Shalini SaxenaA, Kranti MeherC, Madhuri RotellaC, Subhramanyam VangalaC, Satish ChandranC, Nikhil MalhotraB, Ratnakar Palakodeti B, Sreedhara R Voleti A*, and Uday SaxenaC* A In Silico Discovery Research Academic Services (INDRAS) Pvt. Ltd. 44-347/6, Tirumalanagar, Moula Ali, Hyderabad – 500040, TS, India B Tech Mahindra Gateway Building, Apollo Bunder, Mumbai-400001, Maharashtra, India C Reagene Innovation Pvt. Ltd. 18B, ASPIRE-BioNEST, 3rd Floor, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad – 500046, TS, India *Corresponding Authors email address: [email protected] [email protected] Abstract Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The RBD domain of SARS-CoV-2 Spike protein is a promising drug target due to its pivotal role in viral-host attachment. These specific structural domains can be targeted with small molecules or drug to disrupt the viral attachment to the host proteins. In this study, FDA approved Drugbank database were screened using a virtual screening approach and computational chemistry methods. Five drugs were short listed for further profiling based on docking score and binding energies. Further these selected drugs were tested for their in vitro biological activity. There was significant correlation between the prediction from computational studies and the actual RBD-ACE2 binding inhibition by the drugs. Then, we performed a series of studies that mimic some of the biological events seen in COVID-19 patients such as secretion of IL1β, presentation of a more thrombogenic endothelium by production of thrombomodulin and accumulation of inflammatory cells such as monocytes in the lungs. Of all the drugs, most promising drug was Ertugliflozin which is used for type-2 diabetes. This drug possesses several desired properties and may be a good candidate for immediate repurposing for treatment of COVID-19. Keywords: COVID-19, SARS-CoV-2, Virtual screening, Docking, RBD-ACE2, IL1β, ELISA bioRxiv preprint doi: https://doi.org/10.1101/2021.06.18.448921; this version posted June 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1. Introduction World Health Organization has now declared COVID-19 a global pandemic actively spreading around the world. COVID-19 caused by the virus SARS-CoV-2, can cause symptoms such as fever, cough, pneumonia, nausea, and fatigue, and death due to severity of symptoms and associated co-morbidities such as hypertension, diabetes, etc. As of now, SARS-CoV-2 has reached almost all countries around the world, with more than 121 million confirmed cases and around 3 million deaths as of March, 2021 [1]. The mechanism of COVID-19 effect is believed to be that it binds its host’s cellular receptors through, homo viral surface trimeric spike glycoprotein (S-protein) with human host cell surface angiotensin-converting enzyme (hACE2) receptor and membrane fusion, necessary for viral entry into the host cell [2]. The entry of the virus into the host cell requires the spike or S-protein to be cleaved in two steps. The first step is the binding of the virus to the ACE2 protein and this is accomplished by the cellular proteases acting at the region between S1 and S2, namely, the transmembrane serine protease TMPRSS2. S1 and S2 subunits are responsible for viral-receptor binding and virus- host cell membrane fusion, respectively. The S1 subunit bears the receptor-binding domain (RBD) on its C-terminal domain. The RBD itself contains the receptor-binding motif (RBM), which actually comes into contact with the carboxypeptidase domain of the ACE2 molecule. In the spike protein, there is unique furin cleavage site which was not found in SARS-CoV. This site makes the virus more adaptable for cleavage by other cellular proteases as well, thus making it able to infect more cell types. This cleavage step is required for the initiation of membrane fusion by the S2 subunit, and this involves a second site of cleavage on this site, which is now considered essential to activate the S2 protein [3]. Mitigation of COVID-19 by drugs prophylactically and therapeutically has become the focus of pharma industry research. To this end, in early 2020, many anti-viral compounds were proposed [4], natural products were reported [5] and now, vaccines are being developed [6]. It is agreed universally that drug-repurposing is a safe and best approach towards treatment of COVID-19. Drug repurposing refers to the identification of novel applications for an approved or investigational/experimental drug outside the premise of its original indication. At present, this strategy would be a logical choice for developing a new drug for COVID-19 considering the substantial time-scales associated with new drug discovery and the trial-based validation of its safety and efficacy. The major advantage of repurposed drug is that it has been already evaluated for safety in human trials, which would reduce the significant amounts of time and money, a priority concern in SARS-CoV-2 drug development. Application of in silico techniques in early stages of drug discovery either through conventional or repurposing approaches aid in minimizing the chances of the failures. The SARS-CoV-2 virus is closely related to the SARS-CoV and this allows utilization of the known protein structures to quickly build a model for drug discovery to search for possible medications for the SARS-CoV-2. The aim of the present study is to in silico identify clinically approved drugs treating various diseases of human importance, which would then be pharmacologically evaluated for targeting the RBD domain of the S-protein of COVID-19 as well as their anti- inflammatory and anti-thrombogenic properties. The RBD domain of S-protein is an attractive and well characterised drug target in corona viruses owing to the pivotal role it plays in the entry of the virus into the host cell. Targeting this specific structural domain with repurposed drugs to disrupt the COVID-19 viral attachment bioRxiv preprint doi: https://doi.org/10.1101/2021.06.18.448921; this version posted June 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. to the host proteins. Much research has gone into finding drugs that can effectively prevent or reduce viral-ACE2 interactions. Subsequently, testing their binding efficacy in in vitro assays with RBD will elucidate the computational rationale for robust proposal of drug repurposing. Screening the FDA approved drugs and antivirals from the Drugbank database through molecular docking methodology would identify and prioritize repurposed drugs as potential leads in order to avoid any bias towards a particular drug. The drugs identified by virtual screening were then tested in a cell-free biochemical RBD-ACE2 binding study to validate findings from virtual screening. In addition, the drugs were further profiled in cytokine secretion and three dimensional (3D)-printed human-cell-based vascular lung model for potential anti-inflammatory and anti-thrombotic activities which could be useful in treatment of COVID-19. 2. Material and Methods Cresset Flare software was used for molecular docking studies against the spike protein SARS- CoV-2 (http://www.cresset-group.com/flare/) [7]. 2.1 Ligand preparation The 2D structures of all the drugs were downloaded from Drugbank database and prepared using Flare software. Hydrogen atoms were added in the structure and atom force field parameterization was assigned. Further, energy minimized was done for all the drugs, nonpolar hydrogen atoms were merged, and rotatable bonds were defined. Later, ligand minimization has been carried out in Flare by Minimize tool by using Normal calculation methods. Ligands should also be prepared to assign proper bond orders and to generate the correct tautomer and/or ionization state. 2.2 RBD structure preparation The RBD of spike glycoprotein SARS-CoV-2 is used for present study. This RBD binds to ACE2 receptor on the host cell with high affinity, which makes it a key target for the novel coronavirus therapy development. The 3D structure of RBD binds to ACE2 receptor (PDB ID: 6M0J) were downloaded from Protein Data Bank (PDB) (https://www.rcsb.org). The protein has two chain A and E, the A chain has ACE2 receptor and E chain has RBD domain. The RBD domain has been save in to PBD format for further studies. The target protein preparation was carried out in Flare software with default settings. Missing residues, hydrogen's and 3D protonation were carried out on the target protein. Protein minimization has been carried out in Flare by Minimize tool by using Normal calculation methods. 2.3 Computational analysis of binding sites Binding site was generated Accelrys Discovery Studio visualizer 3.5 (Copyright© 2005-12, Accelrys Software Inc.) to explore potential binding sites of the RBD protein using receptor cavities tools. Based on a grid search and “eraser” algorithm, the program defines where a binding site is. The binding sites were displayed as a set of points (point count) and the volume of each of cavity was calculated as the product of the number of site points and the cube of the grid spacing.
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