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Abstract
SARS-CoV-2 has caused millions of infections and more than 600,000 deaths worldwide. Despite the wide number of studies to date, there is no specifically effective treatment available for SARS-CoV-2. However, it has been proposed to target reused drugs with potential antiviral activity to the interfere between the angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) interface of SARS-CoV-2 to avoid cell recognition. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have some type of activity against a wide variety of viruses including SARS-CoV-2. Therefore, we carried out an exhaustive computational biophysical study of various NSAIDs targeting the RBD-ACE2 complex using multiple comparative analysis of docking and molecular dynamics. Only the Ibuprofen (Propionic acid derivative), Aspirin (Salicylate), and the Acetaminophen (p-aminophenol derivative) had a thermodynamically favorable docking with the complex RBD-ACE2 interface under the conditions of this study. Although, Ibuprofen was the NSAIDs most thermodynamically favorable docking in the shortest simulation time, and was the major inducer of structural changes, conformational changes, and overall changes in the complex throughout the simulation, including disturbances in composition and distribution of cavities at the interface. Results that point to ibuprofen as an NSAID that, under the conditions outlined in this investigation, may have the highest probability of generating a disturbance in the stability of the RBD-ACE2 complex. This statement, although it could contribute information for the empirical treatment and prevention of COVID-19, represents only a theoretical orientation and approach, and requires its experimental demonstration because our predictions cannot secure a pharmacologically and clinically relevant interaction. Therefore, our results suggest a possible alternative mechanism of action of some NSAIDs against COVID-19 which is relevant because there are no reports related to this, in addition to their well-known anti-inflammatory properties.
Highlights
The SARS-CoV-2 pandemic has required rapid drug searches for the management of COVID-19 disease
Based on what has been previously described, we propose to perform a computational biophysical characterization of interaction of various non-steroidal anti-inflammatory drugs (NSAIDs)-type compounds at the RBDACE2 complex biointerface and the perturbation energyconformational induce by these drugs on this complex in order to obtain information about possible inhibitory mechanistic routes of these drugs against the SARS-CoV-2 virus, especially since these drugs are not banned to date by the World Health organization (WHO) for the symptomatic treatment of COVID-19
The amino acids that interact at the angiotensin-converting enzymes 2 (ACE2) and receptor binding domain (RBD) interface are in total 15 residues of ACE2 that interact with RBD: these are residues 24 (Q), 27 (T), 30 (D), 31 (K), 34 (H), 35 (E), 37 (E), 38 (D), 41 (Y) and 42 (Q) that are in α1, a residue that comes from α2 and residues 353 (K), 354 (G), 355 (D) and 357 (R) that come from the linker between β3 and β4, as reported [49, 50]
Summary
The SARS-CoV-2 pandemic has required rapid drug searches for the management of COVID-19 disease. COVID-19 is a pathology characterized by an acute viral infection in humans with an average incubation period of 3 days [1] similar to SARS-CoV1 [2]. The development of acute respiratory distress syndrome (ARDS) has been reported in most patients [4,5,6,7]. Patients are prone to a variety of ARDS-related complications, including acute heart injury and secondary infection [8]. It has been pointed out that the use of anti-inflammatory drugs concomitantly with the standard treatments recommended by the World Health organization (WHO) could be useful against COVID-19 [9] including non-steroidal anti-inflammatory drugs (NSAIDs) [10,11,12,13,14]. NSAIDs have been little considered because they have a high degree of safety and have been used in adverse respiratory conditions [15] are associated with various adverse effects [16,17,18]
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