In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies

Abstract

Background Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro). Material and Methods Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals. Results and Discussion From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained. Conclusion In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.

An Integrated Analysis of Mechanistic Insights into Biomolecular Interactions and Molecular Dynamics of Bio-Inspired Cu(II) and Zn(II) Complexes towards DNA/BSA/SARS-CoV-2 3CLpro by Molecular Docking-Based Virtual Screening and FRET Detection

“…In line with several previous studies, the solvent effect was accounted for in the framework of the polarizable continuum model with the support of the integral equation formalism (IEF-PCM) [ 35 , 36 ]. In addition, docking studies were performed using Autodock Vina to acquire insight into the binding profile of all substances into the active sites of BSA, SARS-CoV-2 main protease (Mpro), and CT-DNA dodecamer [ 4 , 37 , 38 , 39 ].…”

Bioinformatics Study of Flavonoids From Genus Erythrina As Ace2 inhibitor Candidates For Covid-19 Treatment

“…These criteria were developed based on the observation that most of the orally active drugs exhibit these properties. [28][29][30] Based on its physicochemical properties, compound 310 had a molecular weight of 390.48 g/mol (<500 Da), four hydrogen-bond acceptors, one hydrogen-bond donor, and a predicted logP of 4.76; compound 471 had a molecular weight of 418.489 g/mol (<500 Da), five hydrogen-bond acceptors, no hydrogen bond-donor, and a predicted log P of 5.67, therefore compounds 310 and 471 met the drug-like criteria of Lipinski's rule of five.…”

The Thiadiazole Ring (THD) Is a Building Block for Potential Inhibitors of the SARS-CoV-2 Main Protease (Mpro): Theoretical Look into the Structure, Reactivity, and Binding Profile of Three 1,3,4-THD Derivatives toward Mpro

“…Mpro is a 33.8-kDa homodimer made of 306 amino acids (AA) in each protomer and encloses three functionals domains denoted as Domain I, II, and III. The active site, situated between the cleft of domains I and II, was defined as in our recent studies [25,26], while the docking exhaustiveness was fixed at 2000 for better atomic flexibility. Finally, best-docked poses were visualized using BIOAVIA Discovery Studio 3 Visualizer [27].…”