Synthesis, DFT investigation, ADME-T properties, molecular docking and molecular dynamics simulation of new α-aminophosphonate inhibitor targeting Mpro and RdRp enzymes in SARS-CoV-2

• Published in: Journal of molecular structure 2024-11, Vol.1315, p.138842, Article 138842
• Main Authors: Kerkour, Rachida, Moumeni, Ouahiba, El houda Rabhi, Nour, Mehri, Mouna, Boublia, Abir, Chafai, Nadjib, Chafaa, Saleh
• Format: Article
• Language: English
• Subjects: ADME-T; DFT; Docking; Mpro; RdRp; SARS–CoV-2; α-Aminophosphonate
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.138842

•A new α- aminophosphonate derivative namely: diethyl [phenyl (pyridine-4-yl amino) methyl] phosphonate (α-DAP) was synthesized using Kabachnik–Fields reaction.•Optimized structure, frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) of α-DAP were performed using (DFT) B3LYP/6–31 G (d, p).•The reactivity of α-DAP was evaluated using frontier orbitals studies.•The inhibition of SARS-CoV-2 main protease and RNA dependent RNA polymerase by α-DAP was predicted by using molecular docking.•The molecular dynamics simulation was conducted to assess the stability of the enzyme-inhibitor complex. A specific α-aminophosphonate molecule, namely diethyl (phenyl (4-pyridinylamino) methyl) phosphonate (α-DAP), as a potential SARS-CoV-2 inhibitor, has been synthesized via a Kabachnick-Fields reaction, a three-component, dalfampridine, benzenecarbaldehyde and triethoxyphosphine, and its molecular structure was confirmed by spectroscopic and physicochemical methods such FT-IR, UV–vis, melting point, 1H NMR, 13C NMR and 31P NMR spectra. The Density Functional Theory (DFT) at the B3LYP/6–31 G (d, p) level was used to calculate the optimized structure, reactivity, stability of the target molecule. In this context, several characteristics have been calculated and the obtained theoretical results are in good agreement with the experimental ones. Also, predicted ADME-T were performed and the obtained parameters indicated that the compound under investigation should have good oral bioavailability. In addition, the molecular docking has been used, further, the compound showed high potential docking with SARS-CoV-2 major protease (Mpro) and RNA dependent RNA polymerase (RdRp). Finally, the molecular dynamics simulation demonstrated the stability of the protein-ligand interaction and offered insights into the specific amino acid residues participating in the binding process.