Tropomyosin receptor kinase (TRK) enzymes are responsible for different types of tumors caused by neurotrophic tyrosine receptor kinase gene fusion and have been identified as an effective target for anticancer therapy. The study of the mechanism between polo-like kinase (PLKs) and pyrazol inhibitors was performed using 3D-QSAR modeling, molecular docking, and MD simulations in order to design high-activity inhibitors. The HQSAR (Q² = 0.793, R² = 0.917, R²_ext = 0.961), CoMFA (Q² = 0.582, R² = 0.722, R²_ext = 0.951), CoMSIA/SE (Q² = 0.603, R² = 0.801, R²_ext = 0.849), and Topomer CoMFA (Q² = 0.726, R² = 0.992, R²_ext = 0.717) showed good reliability and predictability. All models have been successfully tested by external validation, so all five established models are reliable. The analysis of the different contour maps of different models gives structural information to improve the inhibitory function. Molecular docking results show that the amino acids Met 592, GLU 590, LEU 657, VAL 524, and PHE 589 are the active sites of the tropomyosin receptor TRKs. The results obtained by MD showed that compound 19i could form a more stable complex protein (PDB id: 5KVT). Based on these results, we developed new compounds and their expected inhibitory activities. The results of physicochemical and ADME-Tox properties showed that the four proposed molecules are orally bioavailable, and they are not toxic in the Ames test. Thus, these results would provide modeling information that could help experimental researchers find TRK type I inhibitors more efficiently. Communicated by Ramaswamy H. Sarma

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 ${\mathrm{R}}_{\mathrm{pred}}^2$ = 0.683, ${\mathrm{R}}_{\mathrm{pred}}^2$= 0.758, and ${\mathrm{R}}_{\mathrm{pred}}^2$= 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.

Modeling the structural properties of novel morpholine-bearing 1, 5-diaryl-diazole derivatives as potent COX-2 inhibitor, two proposed models based on CoMFA and CoMSIA were evaluated by external and internal validation methods. Partial least squares analysis produced statistically significant models with Q² values of 0.668 and 0.652 for CoMFA and CoMSIA, respectively, and also a significant non-validated correlation coefficient R² with values of 0.882 and 0.878 for CoMFA and CoMSIA, respectively. Both models met the requirements of Golbraikh and Tropsha, which means that both models are consistent with all validation techniques. Analysis of the CoMFA and CoMSIA contribution maps and molecular docking revealed that the R1 substituent has a very significant effect on their biological activity. The most active molecules were evaluated for their thermodynamic stability by performing MD simulations for 100 ns; it was revealed that the designed macromolecular ligand complex with 3LN1 protein exhibits a high degree of structural and conformational stability. Based on these results, we predicted newly designed compounds, which have acceptable oral bioavailability properties and would have high synthetic accessibility.