3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer

Abstract

Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions

“…Several research studies have demonstrated that the addition of nitrogen-containing heterocyclic groups, such as thiazole, pyrazole, pyrimidine, thiadiazole, and triazole, to the surface recognition domain of HDACIs, can significantly enhance their selectivity and inhibitory potency [33]. It has been observed that the N, O, and S atoms, along with the electron-rich nitrogen-containing heterocycle, are capable of forming π-π and hydrogen bonding interactions with the amino acid residues located at the periphery of HDAC catalytic sites [34]. Table 2.…”

3D computer modeling of inhibitors targeting the MCF-7 breast cancer cell line

“…In the present work, we use the three-dimensional quantitative structure–activity relationship (3D-QSAR) with the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors to determine the key characteristics for the potential inhibition of MCF-7 cells by tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives ( Er-rajy et al, 2022 ; Er-rajy et al, 2023a ). In addition, the ADME-Tox (ADMET) studies and pharmacokinetic characteristics were used to predict the pharmaceutical features of the newly designed molecules for aspects crucial to drug effectiveness and pharmacokinetics, including solubility, permeability, and metabolic stability ( Alqahtani, 2017 ).…”