Abstract
BackgroundThe sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19.ResultsMolecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target.ConclusionsHybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.
Highlights
The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society
The three-dimensional structure of the selected compounds was optimized using the classic force field method MMFF94 (Merck Molecular Force Field 94) [26], implanted in the free A vogadro® software [22], programmed to perform a cycle of 4 interactions of the Steepest Descent algorithm, following the parameters defined in Eq (1), where the most stable structure is obtained by minimizing the potential energy (E) of a molecule in its steady state, with the contribution of a force exerted on a bond between two atoms (r − r0) and the sum includes all bonds of the molecule’s three-dimensional space [27]
When the ligands were compared regarding their interactions with main protease (Mpro), it was possible to separate them into two distinct groups (Fig. 3A)
Summary
The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. SARS-CoV-2 possesses a single strand of positive sense RNA as genetic material, which encodes structural capsid proteins, in addition to enzymes. In this context, among different pharmacological targets currently being studied, the main protease (Mpro) stands out, which plays a fundamental role in viral replication. Theoretical studies have identified a region of inhibition of the active fraction of the enzyme, characterized by the formation of a complex between Mpro and the ligand N3. This finding has contributed to the prospection of new drugs in screening in silico [6]
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