Computational approach towards the design of artemisinin–thymoquinone hybrids against main protease of SARS-COV-2

Abstract

Background 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 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. Results Molecular 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. Conclusions Hybrid 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.

RETRACTED: Artemisia Extracts and Artemisinin-Based Antimalarials for COVID-19 Management: Could These Be Effective Antivirals for COVID-19 Treatment?

“…An in vitro study against Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) of various antimalarial drugs showed low antiviral activity for dihydroartemisinin: EC 50 20.1 µmol/L, EC 90 41.9 µmol/L, CC 50 58.9 µmol/L, and SI 3) [115]. Molecular docking, along with in vitro studies of artemisinin-thymoquinone hybrids also demonstrated activity against the main protease of the virus [116].…”

Multidisciplinary approaches for enzyme biocatalysis in pharmaceuticals: protein engineering, computational biology, and nanoarchitectonics

“…These advances are not only driven by biology, but are heavily reliant on computational biology. 103–109 The marriage of computational modeling and biological understanding empowers researchers to predict, manipulate, and optimize enzyme behavior at a molecular level. Furthermore, the integration of nanoarchitectonics into enzyme biocatalysis brings novel strategies for enzyme immobilization, encapsulation, and deployment within custom-designed nanomaterials.…”

“…Another notable application lies in computational enzyme design. 28,34,104,108,109,149 Here, computational biology enables the tailored engineering of enzymes with enhanced catalytic activity and selectivity. Researchers can iteratively model enzyme structures and interactions to predict the effects of mutations, ultimately guiding the development of enzymes optimized for specific reactions.…”

Artemisinins in Combating Viral Infections Like SARS-CoV-2, Inflammation and Cancers and Options to Meet Increased Global Demand

“…Also, other ACTs including artesunate-pyronaridine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine displayed the same range of inhibition (27.1 to 34.1 %) ( Gendrot et al, 2020 ). Along with in vitro studies of ACTs, molecular docking studies have also demonstrated the anti-SARS-CoV-2 activity of artemisinin-thymoquinone hybrids against the main protease of the virus ( de Oliveira et al, 2021 ).…”