Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.

Abel Salazar Institute of Biomedical Sciences University of Porto 4050 313 Porto Portugal

Advanced Polytechnic and University Cooperative University Institute of Health Sciences Avenida Central de Gandra 1317 4585 116 Gandra Portugal

Animal Science Study Centre 4051 401 Porto Portugal

Associate Laboratory for Animal and Veterinary Science 1300 477 Lisboa Portugal

Department of Chemistry Faculty of Science and Engineering Swansea University Swansea SA2 8PP UK

Department of Organic Chemistry University of Chemistry and Technology Prague 166 28 Prague Czech Republic

Epidemiology Research Unit Institute of Public Health University of Porto 4050 091 Porto Portugal

School of Pharmacy and Pharmaceutical Sciences College of Biomedical and Life Sciences Cardiff University Cardiff CF10 3BN UK

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