Potential SARS-CoV-2 RdRp inhibitors of cytidine derivatives: Molecular docking, molecular dynamic simulations, ADMET, and POM analyses for the identification of pharmacophore sites

Abstract

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is one of the optimum targets for antiviral drug design and development. The hydroxyl groups of cytidine structures were modified with different aliphatic and aromatic groups to obtain 5´-O-acyl and 2´,3´-di-O-acyl derivatives, and then, these derivatives were employed in molecular modeling, antiviral prediction, molecular docking, molecular dynamics, pharmacological and POM studies. Density functional theory (DFT) at the B3LYP/6-31G++ level analyzed biochemical behavior and molecular electrostatic potential (MESP) of the modified cytidine derivatives. The antiviral parameters of the mutated derivatives revealed promising drug properties compared with those of standard antiviral drugs. Molecular docking has determined binding affinities and interactions between the cytidine derivatives and SARS-CoV-2 RdRp. The modified derivatives strongly interacted with prime Pro620 and Lys621 residues. The binding conformation and interactions stability were investigated by 200 ns of molecular dynamics simulations and predicted the compounds to firmly dock inside the RdRp binding pocket. Interestingly, the binding residues of the derivatives were revealed in high equilibrium showing an enhanced binding affinity for the molecules. Intermolecular interactions are dominated by both Van der Waals and electrostatic energies. Finally, the pharmacokinetic characterization of the optimized inhibitors confirmed the safety of derivatives due to their improved kinetic properties. The selected cytidine derivatives can be suggested as potential inhibitors against SARS-CoV-2. The POM Theory supports the hypothesis above by confirming the existence of an antiviral (Oδ-—O’δ-) pharmacophore site of Hits.

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

“…Sixteen-proton multiples at δ 1.29 {CH 3 (C H 2 ) 8 (CH 2 ) 2 CO-} and three-proton multiples at δ 0.90 {C H 3 (CH 2 ) 10 CO-} were also seen. These findings rationalize the appearance of a lauroyl group in position 2 as depicted by the deshielding of the C-2 proton from its common value (~4.00) [ 39 , 40 ] in the initial diol ( 2 ) to δ 4.83 (as dd, J = 3.7 Hz, and 9.7 Hz). The 13 C-NMR spectrum also displayed the appearance of a lauroyl group following the prospective resonance peaks: δ 174.61 {CH 3 (CH 2 ) 10 C O-}, δ 34.18, 31.94, 29.64 (×2), 29.50, 29.31, 29.30, 29.02, 24.97, 22.73 {CH 3 ( C H 2 ) 10 CO-} and δ 14.17 { C H 3 (CH 2 ) 10 CO-}.…”

“…The present work has two objectives which are mainly the synthesis of a series of derivatives by substituting the hydroxyl group (-OH) of methyl 4,6- O -benzylidene-α- d -glucopyranoside (MBG) with various acyls groups (including aromatic and heteroaromatic group), followed by an exploration of the characterization of their physicochemical and biological properties using in vitro and in silico methods. It is important to mention that employing the in silico approach could help to provide insightful information for complicated biological systems [ 38 , 39 , 40 ]. After establishing the structure and purity of these new derivatives by employing spectroscopic and chromatography methods, their antibacterial and antifungal activities were evaluated in vitro against five collected strains.…”

Nucleoside‐Based Drug Target with General Antimicrobial Screening and Specific Computational Studies against SARS‐CoV‐2 Main Protease

“…In their research study, Kawsar et al [192] . subjected fourteen cytidine compounds to modification using various aliphatic and aromatic chains ( 127 – 140 ), as shown in Figure 12.…”

“…Analysis based on molecular dynamics simulations. A. RMSD, B. RMSF and C. RoG (radius of gyration) [192].…”

Black seeds (Nigella sativa) for the management of Dengue viral disease: POM analyses for the identification of new antiviral pharmacophore sites

“…The pharmacophore sites exhibiting antifungal properties (O1 δ− ---O2 δ− ) have been validated through atomic charge calculations of compounds. It was observed that these compounds exhibit a greater degree of e cacy as antifungal and antiviral agents than antibacterial agents (Munia et al 2022;Kawsar et al 2022Kawsar et al , 2023.…”