In silico study of the potential interactions of 4′-acetamidechalcones with protein targets in SARS-CoV-2

Abstract

The sanitary emergency generated by the pandemic 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 20 million people were reported with the infection. Of these, more than 740,000 died. In view of the situation, strategies involving the development of new antiviral molecules are extremely important. The present work evaluated, through molecular docking assays, the interactions of 4′-acetamidechalcones with enzymatic and structural targets of SARS-CoV-2 and with the host's ACE2, which is recognized by the virus, facilitating its entry into cells. Therefore, it was observed that, regarding the interactions of chalcones with Main protease (Mpro), the chalcone N-(4′[(2E)-3-(4-flurophenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPF) has the potential for coupling in the same region as the natural inhibitor FJC through strong hydrogen bonding. The formation of two strong hydrogen bonds between N-(4[(2E)-3-(phenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAB) and the NSP16-NSP10 heterodimer methyltransferase was also noted. N-(4[(2E)-3-(4-methoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPM) and N-(4-[(2E)-3-(4-ethoxyphenyl)-1-(phenyl)prop-2-en-1-one]) acetamide (PAAPE) chalcones showed at least one strong intensity interaction of the SPIKE protein. N-(4[(2E)-3-(4-dimetilaminophenyl)-1-(phenyl)-prop-2-en-1-one]) acetamide (PAAPA) chalcone had a better affinity with ACE2, with strong hydrogen interactions. Together, our results suggest that 4′-acetamidechalcones inhibit the interaction of the virus with host cells through binding to ACE2 or SPIKE protein, probably generating a steric impediment. In addition, chalcones have an affinity for important enzymes in post-translational processes, interfering with viral replication.

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

“…Mpro SARS-CoV-2 remaining parameters were set as standard. For Mpro SARS-CoV-2 were used 3-way multithreading and the following parameters: center_ x = − 26.734, center_ y = 13.009, center_ z = 56.185, size_ x = 94, size_ y = 112, size_ z = 108, spacing = 0.642 [ 29 ]. Non-protein molecules were removed, and polar hydrogen were added using AutoDock Tools 1.5.6 software (ADT, http://mgltools.scripps.edu/ ) [ 30 ].…”

“…The pharmacokinetics of the compounds were estimated by predictive parameters of absorption, distribution, metabolism and excretion (ADME) at pH 7.4 through the preADMET server ( https://preadmet.bmdrc.kr/ ). The following were evaluated: human intestinal absorption (HIA) [ 35 ]; permeability through the intestinal epithelium, using the Caco-2 model [ 30 , 32 ]; plasma protein binding (PPB) [ 36 ]; permeability through the blood–brain barrier (BBB) [ 29 , 33 ]; and interaction with cytochrome P450 (CYP450) enzymes. The toxicity parameters analyzed were: mutagenicity and carcinogenicity, both using the Ames test [ 37 ]; and cardiotoxicity, by inhibition of the hERG potassium channel (Human Ether-a-go-go-Related Gene).…”

Molecular docking identification for the efficacy of natural limonoids against COVID-19 virus main protease

“…1 ). The parameters used were: center_x = -26.734, center_y = 13.009, center_z = 56.185, size_x = 94, size_y = 112, size_z = 108, spacing = 0.642 and exhaustiveness = 8. using code AutodockTools version 1.5.6 [ 14 ], polar hydrogens from Mpro and ions were added[ [15] , [16] , [17] ].

Figure 1 grid box parameters used to perform a simulation.

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The Unique Australian Flora, A Veritable Pandora’s Pharmacopeia of Compounds with Therapeutic Biomedical Potential: Are the Chalcones the Geni in The Box?

“…Interaction of these flavonoids with ACE2 may also impede the binding of SARS-CoV-2 spike protein and is in line with the anti-viral properties of these compounds [149].The interaction of flavonoids with Mpro, Spike receptor binding domain (Spike-RBD), RNA -dependent RNA polymerase (RdRp or Nsp12), non-structural protein 15 (Nsp15) and the host ACE-2 spike-RBD binding domain have been examined using advanced computation molecular docking techniques. These en-silicoSARS-CoV-2 binding studies indicated that tribuloside, legalon and isosilybin had anti-viral antiinfective properties, warranting further evaluation to determine how effective they are in the inhibition of SARS-CoV-2 infectivity [150].A range of chalcone derivatives have been evaluated using molecular docking methods to assess the effectiveness of these re-purposed compounds on the prevention of the infectivity and replication of SARS-CoV-2 [151][152][153][154][155].…”