Thermochemical, PASS, Molecular Docking, Drug-Likeness and In Silico ADMET Prediction of Cytidine Derivatives against HIV-1 Reverse Transcriptase

Abstract

In recent, millions of people are living with the human immunodeficiency virus type 1 (HIV-1), which causes acquired immunodeficiency syndrome. HIV-1 reverse transcriptase (RT) is one of the main viral targets for HIV-1 inhibition. Pyrimidine nucleoside derivative, 3′-azido-3′-deoxythymidine (AZT) is a highly active nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). In this work, hydroxyl (-OH) groups of cytidine structure were modified with different aliphatic and aromatic groups to get 5´-O-acyl- and 2´,3´-di-O-acyl derivatives and then employed for molecular modeling, molecular docking, biological prediction, and pharmacological studies. Herein, we relate the optimization of cytidine and its acylated analogues applying density functional theory (DFT) with B3LYP/3-21G level theory to explore their thermochemical and molecular electrostatic potential (MEP) properties. Prediction of activity spectra for substances (PASS) indicated promising antiviral, anti-carcinogenic, and antifungal functionality of these cytidine esters compared to the antibacterial activities. To support this observation, their cytotoxic prediction and molecular docking studies have been performed against HIV-1 reverse transcriptase (RT) (PDB: 3V4I). Most of the molecules studied out here could bind near the crucial catalytic binding site, Tyr181, Ile94, Ile382, Lys374, Val381, Val90, and Tyr34 of the HIV-1 reverse transcriptase (RT), and the molecules were surrounded by other active site residues like Gln332, Trp406, Asn265, Gly93, His96, Pro95, and Thr165. Finally, these novel molecules were analyzed for their pharmacokinetic properties which expressed that the combination of in silico ADMET prediction, toxicity prediction, and drug-likeness had shown a promising result. The study discusses the performance of molecular docking to suggest the novel molecules active against resistance mutants of RT and/or recombinant strains of HIV-1.

Synthesis, Antimicrobial, Anticancer, PASS, Molecular Docking, Molecular Dynamic Simulations & Pharmacokinetic Predictions of Some Methyl β-D-Galactopyranoside Analogs

“…Quantum mechanical methods are widely used in computational chemistry to calculate thermal, molecular orbital, and molecular electrostatic properties [47]. The Gaussian 09 program [48] is used to optimize the geometry and modify all synthesized analogs further.…”

Antifungal potential of mannopyranoside derivatives through computational and molecular docking studies against Candida albicans 1IYL and 1AI9 proteins

“…Furthermore, regioselective acylation and antimicrobial activity screening of carbohydrate compounds revealed that the attachment of heterocyclic aromatic rings to electron-attracting or donating groups significantly improves the biological properties of the precursor molecules [20][21][22] . The addition of aliphatic and aromatic groups to the hydroxyl group of nucleoside and monosaccharide structures has resulted in the formation of effective antiviral [23][24][25][26][27] and antibacterial candidates 28,29 . Keeping these characteristics in mind, as well as the future goal of discovering novel drug agents [30][31][32][33][34][35][36] with biological importance [37][38][39][40][41][42] , we reported the computational investigation of a number of methyl α-D-mannopyranoside-based analogs 2-7 with some rarely used aliphatic and aromatic groups, including molecular docking against bacterial and fungal proteins.…”

Efficient Antibacterial/Antifungal Activities: Synthesis, Molecular Docking, Molecular Dynamics, Pharmacokinetic, and Binding Free Energy of Galactopyranoside Derivatives

“…In the current investigation, the number of monosaccharide analogs were found to show notable inhibitory activity against cancer cells [22]. The attachment of aliphatic and aromatic groups to modify the hydroxyl group of the nucleoside and monosaccharide structure has been worthwhile in the development of potent antiviral [23][24][25][26][27][28] and antimicrobial candidates [28,29]. Keeping these features in mind, as well as the future target of searching for novel drug agents [30][31][32][33][34][35][36], in this investigation, we reported the biological screening of a number of β-MGP-based analogs 2-10 with some rarely used aliphatic and aromatic groups against seven pathogens, including molecular docking against the bacterial and fungal proteins.…”