In silico study of the interactions of Pilocarpus microphyllus imidazolic alkaloids with the main protease (M^pro) of SARS-CoV-2

Abstract

The disease outbreak caused by SARS-CoV-2 continues to rise worldwide, even in countries which have considered it controlled. As new cases appear daily, infecting millions of people and causing thousands of deaths, the current in silico study aims to investigate the imidazolic alkaloids of the species Pilocarpus microphyllus (Jaborandi) as a potential inhibitory activity against the M pro protease from SARS-CoV-2, since it plays a fundamental role in the processing of polyproteins that are translated from viral RNA. Jaborandi is distributed in some Brazilian biomes, being easily identified, yet little researched, with proven anti-inflammatory, contraceptive, anti-diabetic and gastroprotective activities. In this work, DFT calculation of thermodynamic properties, electrostatic potential surface, frontier molecular orbitals and descriptors of chemical reactivity of imidazolic alkaloids were associated with the use of molecular docking techniques, molecular dynamics and ADMET predictions. One can verify a good reactivity chemistry and energetic stability of epiisopiloturine, epiisopilosine, isopilosine and e pilosine with some residues of amino acids present in the active site of the main protease of COVID-19. In this sense, the results point out to the imidazolic alkaloids of Jaborandi as promising targets for in vitro and in vivo tests, as possible candidates for inhibitors of the enzyme M pro .

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…Yadav et al suggested the higher reactivity of favipiravir toward Mpro since the presence of electron donor and receptor groups in favipiravir displayed the capability of forming a complex with the external target molecule. Other similar studies include refs and − . DFT calculations by Aitouna et al , indicated the epoxidation reaction of parthenolide and himachalene derivatives presented high chemoselectivity.…”

“…Among them, the best one was bisoctrizole . Additionally, some diaminobenzophenone derivatives, prototypical-ketoamide inhibitors, HIV protease inhibitors, leucoefdin, nutraceuticals, and others were also studied. ,,,,− Notably, Mohammad et al optimized some complexes of Mpro with ligands in the protein data bank (PDB) and rescored them by AutoDock Vina, with the best PDB structure being 6M2N.…”

The naturally‐derived alkaloids as a potential treatment for COVID‐19: A scoping review

“…Noscapine, leuconicine F, nigellidine, epiisopiloturine, camptothecin, anisotine, norboldine were also analyzed through molecular docking for Mpro target (de Sá et al, 2021 ; Devasia et al, 2021 ; Firdiana et al, 2021 ; Ghosh, Chakraborty, Biswas, & Chowdhuri, 2020 ; Jade et al, 2021 ; D. Kumar, Kumari et al, 2020 ; N. Kumar, Sood, van der Spek, Sharma, & Chandra, 2020 ; Maiti et al, 2020 ).…”

Alkaloids as Potential Phytochemicals against SARS-CoV-2: Approaches to the Associated Pivotal Mechanisms

“…Also, in another study on Pilocarpus microphyllus alkaloids (Rutaceae), epiisopiloturine showed a suitable interaction with Mpro (−7.0 kcal/mol). Nevertheless, this imidazolic alkaloid was detected as a mutagenic compound in the analysis of ADMET parameters (Ames test) [ 90 ].…”