A Computational QSAR, Molecular Docking and In Vitro Cytotoxicity Study of Novel Thiouracil-Based Drugs with Anticancer Activity against Human-DNA Topoisomerase II

Abstract

Computational chemistry, molecular docking, and drug design approaches, combined with the biochemical evaluation of the antitumor activity of selected derivatives of the thiouracil-based dihydroindeno pyrido pyrimidines against topoisomerase I and II. The IC50 of other cell lines including the normal human lung cell line W138, lung cancer cell line, A549, breast cancer cell line, MCF-7, cervical cancer, HeLa, and liver cancer cell line HepG2 was evaluated using biochemical methods. The global reactivity descriptors and physicochemical parameters were computed, showing good agreement with the Lipinski and Veber’s rules of the drug criteria. The molecular docking study of the ligands with the topoisomerase protein provides the binding sites, binding energies, and deactivation constant for the inhibition pocket. Various biochemical methods were used to evaluate the IC50 of the cell lines. The QSAR model was developed for colorectal cell line HCT as a case study. Four QSAR statistical models were predicted between the IC50 of the colorectal cell line HCT to correlate the anticancer activity and the computed physicochemical and quantum chemical global reactivity descriptors. The predictive power of the models indicates a good correlation between the observed and the predicted activity.

Discovery of Norisoboldine Analogue III11 as a Novel and Potent Aryl Hydrocarbon Receptor Agonist for the Treatment of Ulcerative Colitis

“…The pharmacokinetic (PK) profile (absorption, distribution, metabolism, and excretion, ADME) of the compound was strongly influenced by its physicochemical properties. 24 The ClogP value for each candidate was calculated using ChemBioDraw software (Table S2). NOR had a ClogP value of 1.683.…”

“…After docking, 26 candidate molecules with Δ G < −6.8 kcal/mol and Ki < 10 μM (in which 9 molecules had a Δ G < −7.5 kcal/mol and 4 molecules had a Δ G < −8.0 kcal/mol) were screened as compounds with binding activity. The pharmacokinetic (PK) profile (absorption, distribution, metabolism, and excretion, ADME) of the compound was strongly influenced by its physicochemical properties . The ClogP value for each candidate was calculated using ChemBioDraw software (Table S2).…”

Antibacterial Activity of Quinoline‐Based Derivatives against Methicillin‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa: Design, Synthesis, DFT and Molecular Dynamic Simulations

“…In the Conceptual DFT (CDFT), quantum descriptors including chemical hardness (η), chemical potential (V), and electronegativity (χ) are determined by the molecule response to changes in the electron number (N) at constant external potential, v(r). [54,58]…”

Support Vector Machine based prediction models for drug repurposing and designing novel drugs for colorectal cancer

“…Recently, many new targets have been used for drug development using 3D-QSAR models. The recently published drug targets are Interleukin-6, and DNA Topoisomerase II, where 3D-QSAR models have been developed for CRC to find drugs that show anticancer activity[6,7]. Likewise, in this study, we have developed QSAR models for 12 CRC cell lines to identify putative drugs for CRC.…”