Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Abstract

Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q2 = 0.823, r2 = 0.979; CoMSIA model: q2 = 0.804, r2 = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisf actory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Structural optimizations on this portion should be helpful for the further potency improvement. Aimed at investigating the SAR of indolocarbazoles as Tie‐2 inhibitors, Zhang and co‐workers elucidated the detail hydrogen bonds between the inhibitors and Tie‐2 . The hydrogen bond sites on the surface were a powerful tool for design of novel inhibitors.…”

“…Aimed at investigating the SAR of indolocarbazoles as Tie-2 inhibitors, Zhang and co-workers elucidated the detail hydrogen bonds between the inhibitors and Tie-2. 133 The hydrogen bond sites on the surface were a powerful tool for design of novel inhibitors. Their results not only helped to comprehend the act mechanism of indolocarbazoles, but also provided new information for design of Tie-2 inhibitors.…”

Fragment‐ and negative image‐based screening of phosphodiesterase 10A inhibitors

“…The ligand‐based methods such as pharmacophore (PHA) and three‐dimensional quantitative structure–activity relationship (3D‐QSAR) modeling, which rely on the advance knowledge of active compounds, are computationally inexpensive. However, despite being commonly used in the drug discovery and lead optimization, the PHA and 3D‐QSAR model generation does not necessarily utilize the bioactive ligand conformers but those that generate the most explanatory model(s) (Cramer, Patterson, & Bunce, ; Kinase, Zhang, Li, Zhang, & Ai, ; Lowe, Ferrebee, Rodriguez, Conn, & Meiler, ; Niinivehmas et al., ; Patel, Noolvi, & Sharma, ; Shubina, Niinivehmas, & Pentikäinen, ; Tian et al., ; Yadav et al., ). In contrast, the structure‐based methods such as flexible molecular docking, which attempt to predict the ligand's bioactive binding pose and estimate its binding energy, rely solely on the target protein's 3D structure and require a lot of computational resources (Niinivehmas et al., ; Nurminen et al., ; Shubina et al., ).…”