Sarkar Mohammad Abe Kawsar, Tahmida Shamsuddin, Mohammed Anowar Hosen, Muhammad Shaiful Alam, Talha Bin Emran

Uridine derivatives: Antifungal, PASS outcomes, ADME/T, drug-likeliness, molecular docking and binding energy calculations

Several nucleoside derivatives are used as antifungal, antiviral, antibacterial, and anticancer agents and have shown effective results against fungal, bacteria, viruses, and cancer. In this investigation, we have identified the biological and quantum chemical activities of our previously published synthesized uridine derivatives by in silico approached. The in silico study demonstrated ADME/T (absorption, distribution, metabolism, elimination, toxicity) analysis, drug likeliness test, PASS (prediction of activity spectra for substances) parameter, molecular docking, non-bond interaction, and MM-GBSA (molecular mechanics/generalized born surface area). binding energy calculations. Both the prediction of ADME/T and drug likeliness interpreted for the pharmacokinetics and drug ability of the derivatives. The PASS illustrated that these nucleoside derivatives have shown antifungal and antiviral activity. Besides, molecular docking with a fungal target sterol 14α-demethylase confirmed the antifungal activity that showed a more negative score than two standards, VNI and ampicillin. Compound 7 (5'-O-N-acetylsulfanilyl-2´,3´-di-O-lauroyluridine) showed the highest docking score (-13.108 kcal/mol), while the parent compound showed the lowest (-6.749 kcal/mol). Non-bonding interaction analysis revealed that compound 7 showed a conventional hydrogen bond with ARG (Arginine) 378, a carbon-hydrogen bond with SER (Serine) 311, a pi-sulfur bond, five alkyl bonds, and four pi-alkyl bonds to the active site. On the other hand, compound 14 [5´-O-N-acetylsulfanilyl-2´,3´-di-O-(2,6-dichlorobenzoyl)uridine] showed four conventional hydrogen bonds with HIS (Histidine) 310, ARG (Arginine) 378, ILE (Isoleucine) 464, and HIS (Histidine) 461, a carbon-hydrogen bond, two pi-pi-T-shaped, eight alkyl bonds, and seven pi-alkyl bonds with the active site. MM-GBSA binding energy estimation is performed and compared with two standard drugs, VNI and ampicillin.

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