ABSTRACT
Monosaccharide derivatives are of importance in the field of carbohydrate chemistry because of their effectiveness in the synthesis of biologically active products. As a consequence, the chemistry and biochemistry of carbohydrate derivatives are an essential part of biochemical and medicinal research. In this work, we have explored the speciation of acylated methyl 6-O-myristoyl-α-D-glucopyranoside derivatives (2−9) to find the pharmacodynamics, toxicity profiles, and biological activities by using ADMET studies. PASS prediction also indicated that these acylated derivatives (2−9) are more potent as anticarcinogenic agents than as antioxidant agents. Quantum mechanical study employing density functional theory with B3LYP/6-31G(d,p) for investigating the enthalpies (ΔH), Gibbs free energies (ΔG), entropies (ΔS), and molecular orbital (HOMO−LUMO gap, hardness, softness, chemical potential, and electrophilicity index), dipole moment and natural bond orbital revealed that these derivatives are thermodynamically stable. The molecular docking study revealed that ivermectin has the highest binding affinity (−8.1 kcal mol−1) and, among the tested compounds, 2 and 3 (−5.7 kcal mol−1) showed the highest binding affinity, followed by 4 and 5 (−5.5 kcal mol−1). These results of acylated derivatives (2−9) could be useful for the development of drugs. © 2022, Department of Science and Technology. All rights reserved.
ABSTRACT
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a beta coronavirus that was first found during the Wuhan COVID-19 (coronavirus disease 2019) epidemic in 2019 and listed as a potential global health threat by WHO due to high mortality. The main protease of SARS-CoV-2 is one of the best targets to design and develop antiviral drugs. Nucleoside agents have been under investigation for many years and some of the most clinically effective antiviral agents currently in use are purine or pyrimidine nucleoside derivatives. For example, ribavirin, a synthetic nucleoside similar in structure to guanosine and inosine, has potent in vitro activity against a broad spectrum of viruses, including the epidemic respiratory viruses. Azidothymidine (AZT) is one of the most popular antiviral drugs in which 3'-hydroxyl (-OH) of thymidine is modified by an azide group and now it is used worldwide for the treatment of HIV infection. In this study, several thymidine derivatives with different aliphatic and aromatic groups were subjected to quantum mechanical calculation (QMC), PASS (prediction of activity spectra for substances) antiviral divination, molecular docking, and pharmacokinetic characterization to assess the binding affinity and interaction of thymidine derivatives against main protease (Mpro) of SARS-CoV-2. Density functional theory (DFT) at the B3LYP/3-21G level of theory was employed to enumerate charge distribution, polarizability, and thermodynamic properties such as frontier orbital energy, Gibbs free energy, enthalpy, electronic energy, heat capacity, entropy, of modified derivatives to evaluate the effect of certain groups (aliphatic and aromatic) on the drug properties and found that all derivatives were thermodynamically more stable than the parent molecule thymidine. PASS antiviral parameters of the modified derivatives revealed promising drug properties in comparison to standard antiviral drugs. Molecular docking is performed using AutoDock Vina to determine the binding affinities and interactions between the thymidine derivatives and the SARS-CoV-2 main protease. The modified derivatives strongly interact with the prime Cys145 and His41 residues. Finally, the pharmacokinetic characterization of the optimized inhibitor demonstrates that these thymidine derivatives appear to be safer inhibitors and a combination of in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction and drug-likeness had promising results due to their improved kinetic properties. After all, our comprehensive computational and statistical analysis shows that these selected thymidine derivatives can be used as potential inhibitors against the SARS-CoV-2. © 2021 Nova Science Publishers, Inc.
ABSTRACT
Various clinical trials are undergoing to identify specific drugs for the treatment of new global threat viruses. The main protease of SARS-CoV-2 is one of the significant targets to design and amplify antiviral drugs. In this investigation, we optimized a nucleoside, uridine, and some of its acylated derivatives (2-14) using density functional theory (DFT) at the B3LYP/3-21G level of theory. Charge distribution, polarizability, and thermodynamic properties such as free energy, heat capacity, entropy, of modified compounds were studied in the subsequent analysis to evaluate how certain groups (aliphatic and aromatic) impact the drug properties. It was observed that all derivatives were thermodynamically more stable than the parent ligand, uridine, and some of them were more chemically reactive than others. Then, molecular docking was performed against SARS-CoV-2 main protease (PDB: 6Y84 and 6LU7) to investigate the binding mode (s) and binding affinities of the selected uridine derivatives. Most of the compounds studied here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease and surrounded by other active site residues such as GLY143, MET49, MET165, HIS163, PRO168, GLU166, GLN189 and SER144. Significant binding affinities (-6.0 to -7.8 kcal mol(-1)) for 6LU7 and (-5.9 to -7.7 kcal mol(-1)) for 6Y84 were found which revealed the potency of inhibition of uridine derivatives against SARS-CoV-2 M-pro. Finally, all the modified uridine derivatives were analyzed in silico ADMET and drug-like properties. Overall, the present study could be helpful for the development of uridine-based novel potential inhibitors against the SARS-CoV-2 M-pro.