Inhibitory activity of FDA-approved drugs cetilistat, abiraterone, diiodohydroxyquinoline, bexarotene, remdesivir, and hydroxychloroquine on COVID-19 main protease and human ACE2 receptor: A comparative in silico approach

Abstract

By September 1, 2021, SARS-CoV-2, a respiratory virus that prompted Coronavirus Disease in 2019, had infected approximately 218,567,442 patients and claimed 4,534,151 lives. There are currently no specific treatments available for this lethal virus, although several drugs, including remdesivir and hydroxychloroquine, have been tested. The purpose of this study is to assess the activity of FDA-approved drugs cetilistat, abiraterone, diiodohydroxyquinoline, bexarotene, remdesivir, and hydroxychloroquine as potential SARS-CoV-2 main protease inhibitors. Additionally, this study aims to provide insight into the development of potential inhibitors that may inhibit ACE2, thereby preventing SARS-CoV-2 entry into the host cell and infection. To this end, remdesivir and hydroxychloroquine were used as comparator drugs. The calculations revealed that cetilistat, abiraterone, diiodohydroxyquinoline, and bexarotene inhibit main protease and ACE2 receptors more effectively than the well-known drug hydroxychloroquine when used against COVID-19. Meanwhile, bexarotene and cetilistat bind more tightly to the SARS-CoV-2 main protease and the ACE2 receptor, respectively, than remdesivir, a potential treatment for COVID-19 that is the first FDA-approved drug against this virus. As a result, the molecular dynamic simulations of these two drugs in the presence of proteins were investigated. The MD simulation results demonstrated that these drugs interact to stabilize the systems, allowing them to be used as effective inhibitors of these proteins. Meanwhile, bexarotene, abiraterone, cetilistat, and diiodohydroxyquinoline's systemic effects should be further investigated in suitable ex vivo human organ culture or organoids, animal models, or clinical trials.

Repurposing FDA-approved drugs cetilistat, abiraterone, diiodohydroxyquinoline, bexarotene, and remdesivir as potential inhibitors against RNA dependent RNA polymerase of SARS-CoV-2: A comparative in silico perspective

“…Because of its critical role in virus replication, RdRp is considered a key target for developing antiviral drugs [ 18 , 30 , 31 ]. We recently reported the in-silico screening of bexarotene, diiodohydroxyquinoline, abiraterone, cetilistat, and remdesivir against different SARS-CoV-2 drug targets [ 32 ]. However, RdRp, an important drug target, was excluded from this study.…”

Enzymes in the time of COVID‐19: An overview about the effects in the human body, enzyme market, and perspectives for new drugs

“…The fifth way concerns administration of ACE2 inhibitors, such as dalbavancin, a lipoglycopetide antibiotic 87 ; enalaprilat, an ACE inhibitor 88 ; ledipasvir 89 and paritaprevir, 89 two direct‐acting antiviral drugs used to treat chronic hepatitis C; and cetilistat, an antipancreatic lipase used to treat obesity. 90 Dalbavancin is a drug approved by the FDA that binds to ACE2 and prevents it from interacting with SARS‐CoV‐2 S protein‐based on in silico analysis. 87 Indeed, dalbavancin interacts with ACE2 through four amino acid residues, Glu329, Gln325, Gln42, and Asp38, which are important to the binding of the S protein.…”

“… 89 Such negative energy results indicate that the molecules have a strong affinity for the enzyme pocket. 90 Cetilistat was seen in silico as a potential drug to inhibit ACE2 due to its high binding energy (−8.70 kcal/mol), which suggests that a stable complex is formed between the enzyme and the drug. 90 It is noteworthy that, although dalbavancin, 87 enalaprilat, 88 ledipasvir, 89 paritaprevir, 89 and cetilistat 90 are in FDA‐approved drugs list, safety and dosage in patients infected with SARS‐CoV‐2 should be analyzed before the drugs are administered.…”

“…Ledipasvir and paritaprevir bindings to ACE2 were studied in silico, revealing that these drugs interact with the enzyme with high binding energy −399.338 kJ/mol and −377.593 kJ/mol, respectively 89 . Such negative energy results indicate that the molecules have a strong affinity for the enzyme pocket 90 . Cetilistat was seen in silico as a potential drug to inhibit ACE2 due to its high binding energy (−8.70 kcal/mol), which suggests that a stable complex is formed between the enzyme and the drug 90 .…”

Determination of Alteration in Micromeritic Properties of a Solid Dispersion: Brunauer-Emmett-Teller Based Adsorption and Other Structured Approaches

“…BEX has shown a synergistic effect with Docetaxel in Castrate-resistant prostate cancer inhibiting cyclinB1 and CDK1 expression levels [19]. Recently, this drug has also been found to be effective against COVID-19 virus (SARS-CoV-2) [20][21][22].…”