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Severe Acute Respiratory Syndrome Corona virus 2 (SARS-CoV-2), the virus that causes the disease (COVID-19), has spread rapidly around the world since emerging in Wuhan, China, in late 2019 (Li et al., 2020). The disease is transmitted by inhalation of droplets or contact with infected patients and the incubation period ranges from 2-14 days. The symptoms are usually fever, cough, sore throat, breathlessness, fatigue and pneumonia.
Corona viruses are large, spherical, enveloped positive sense, single stranded RNA viruses from the Latin “Corona”, which means crown or halo (Tyrreii et al., 1996). Four different types of corona viruses exist; they are alpha, beta, gamma, and delta. Alpha and beta are known to originate from bats, whereas gamma and delta have pigs as an origin (Corman et al., 2018). Over the past two decades two novel corona viruses named severe acute respiratory syndrome corona virus (SARS-CoV) and Middle East respiratory syndrome corona virus (MERS-CoV), have emerged and caused severe human diseases (He et al., 2020). Severe acute respiratory syndrome corona virus 2(SARS-CoV-2) belongs to the family of Corona viridae, genus beta corona virus. It exhibits the same structural and molecular pattern as other corona viruses, such as structural proteins S (spike), E (envelope), M (membrane) and N (nucleocapsid). The S protein of SAR-CoV-2 utilizes the host ACE-2 as their receptor to enter into the host cell. Numerous therapeutic strategies are being explored to inhibit SAR-CoV-2 entry, including blocking ACE-2 engagement, inactivating host protease, and inhibiting S2-mediated membrane fusion. So, here the authors have selected the 2019-nCoV RBD/ACE-2-B0AT1 complex as the drug target. The crystal structure PDB ID: 6M17, from the protein data bank is used here to find a suitable ligand against it (Yan et al., 2020).
Several clinical trials have shown chloroquine phosphate, an aminoquinoline used in malaria treatment, to be effective against COVID-19 at a dose of 500mg/day (Kumar et al., 2021, Gao et al., 2020). Chloroquine phosphate also played a promising role in the management of the Zika virus and SARS-CoV outbreak. Chloroquine (CQ) acts by increasing the pH of intracellular vacuoles and altering protein degradation pathway through acidic hydrolases in the lysosomes, macromolecule synthesis in the endosomes, and post-translational protein modification in Golgi apparatus. (Plantone et al., 2018) In addition, chloroquine alters the glycosylation of the cellular receptor of the coronavirus. Hydroxychloroquine (HCQ), a less toxic aminoquinoline, has an N-hydroxyethyl side chain is more soluble than chloroquine (Liu et al., 2020). Similar to chloroquine, hydroxychloroquine increases the pH and confers the antiviral effect. In this study, authors tried designing different derivatives of CQ and HCQ by making changes mainly in the quinolone ring and the diethyl side chain to increase the activity of drug against COVID-19. These compounds were then subjected to docking and binding free energy studies after which the ADME analysis of top 10 compounds was carried out. The best 3 compounds in complex with protein were then evaluated for their stability by MD simulation using Desmond (Schrödinger Release 2020-3)