Repurposing FDA-approved drugs against multiple proteins of SARS-CoV-2: An in silico study

Abstract

The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent need for the right therapeutic drug to curb the disease. However, there is time constraint in drug development, hence the need for drug repurposing approach, a relatively fast and less expensive alternative. In this study, 1,100 Food and Drug Administration (FDA) approved drugs were obtained from DrugBank and trimmed to 791 ligands based on illicitness, withdrawal from the market, being chemical agents rather than drugs, being investigational drugs and having molecular weight greater than 500 (Kg/mol). The ligands were docked against six drug targets of the novel SARS CoV-2 - 3-chymotrypsin-like protease (3CLpro), Angiotensin-converting enzyme (ACE2), ADP ribose phosphatase of NSP3 (NSP3), NSP9 RNA binding protein (NSP9), RNA dependent RNA polymerase (RdRp) and Replicase Polyprotein 1a (RP1a). UCSF Chimera, PyRx and Discovery Studio, were used to prepare the proteins, dock the ligands and visualize the complexes, respectively. Remdesivir, Lopinavir and Hydroxychloroquine were used as reference drugs. Pharmacokinetic properties of the ligands were obtained using AdmetSAR. The binding energies of the standard drugs ranged from -5.4 to -8.7 kcal/mol while over 400 of the ligands screened showed binding energy lower than -5.4 kcal/mol. Out of the 791 number of compounds docked, 10, 91, 132, 92, 54 and 96 compounds showed lower binding energies than all the controls against 3CLPro, ACE2, NSP3, NSP9, RP1a and RdRp, respectively. Ligands that bound all target proteins, and showed the lowest binding energies with good ADMET properties and particularly showed the lowest binding against ACE2 are ethynodiol diacetate (-15.6 kcal/mol), methylnaltrexone (-15.5 kcal/mol), ketazolam (-14.5 kcal/mol) and naloxone (-13.6 kcal/mol). Further investigations are recommended for ethynodiol diacetate, methylnaltrexone, ketazolam and naloxone through preclinical and clinical studies to ascertain their effectiveness.

Targeting human thymidylate synthase: Ensemble-based virtual screening for drug repositioning and the role of water

“…Lumacaftor has a good tolerability pro le [106]. The drug Lumacaftor showed a potential for repurposing against several targets including SARS-Cov-2, C. albicans dihydrofolate reductase and autophagy related 4A cysteine peptidase [107][108][109][110][111][112]. On the other hand, Naldemedine is a peripherally acting µ-opioid receptor antagonist used in the treatment of opioidinduced adverse effects such as constipation, nausea and vomiting [113,114].…”

Evaluation of Receptor Relationships of Some Drugs Used in the Treatment of COVID-19 by Modeling Studies

“…16,17 Molecular docking is one of the main constituents of these techniques and widely used to understand the interactions between ligands and target proteins, allowing us to predict the structure of the ligand-receptor complex. [17][18][19] In this sudy, molecular docking studies were performed to analyze the interactions of drugs that are Dexamethasone, Favipiravir and Hydroxychloroquine which are used in the treatment of COVID-19, with ER, PR and HER2 receptors. According to the results, hydroxychloroquine binds to all three of these recep-tors with the highest affinity, while Dexamethasone binds to the active sites of ER and HER2 receptors with the lowest affinity among these three drugs.…”

“…Molecular docking studies using either of these drugs in previous studies in the literature have generally investigated the binding of drugs to a SARS-CoV-2 protein. 18,[20][21][22] Celik et al analyzed the interactions of both hydroxychloroquine and chloroquine with proteins of SARS-CoV-2 such as SARS-CoV-2 RNA polymerase, main protease and spike proteins which play an important role in the structure, survival, reproduction, attachment and survival of the SARS-CoV-2 virus. 20 They showed that neither hydroxychloroquine nor chloroquine do not act on SARS-CoV-2 proteins however both molecules prevent the binding of SARS CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2) by inter-acting with the allosteric site.…”

Protein–RNA interactions: from mass spectrometry to drug discovery

“…Finding the suitable ligand is based on a virtual screening of molecular libraries, which contain data obtained by the above-mentioned traditional techniques. High-throughput screening is performed based on algorithms that use protein properties and binding site information to select the suitable molecules with desired protein specificity and affinity [ 78 , 79 ]. In addition to this, molecular-docking simulations allow protein–ligand interaction predictions at the structural and thermodynamic level [ 80 ].…”