Identification of defactinib derivatives targeting focal adhesion kinase using ensemble docking, molecular dynamics simulations and binding free energy calculations

Guo, Chuan; Li, Qinxuan; Xiao, Jiujia; Feng, Mang; Xia, Xun; Shi, Mingsong

doi:10.1080/07391102.2022.2135601

Cited by 2 publications

(3 citation statements)

References 153 publications

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“…Interestingly, there are two regions of human SIK3 with siginifacance fluctuations ( Supplementary Figure S21 ), that is, the regions at positions 206–232 (T-loop) and 344–384 (UBA) ( Figure 5 ). The conformation of the T-loop was different from the crystal structures of protein kinases; for instance, human FAK may exhibit open or closed T-loop conformation while binding with FAK-inhibitors ( Supplementary Figure S22 ) ( Guo et al, 2022 ). The T-loop was phosphorylated to activate the kinase domain and to regulate the downstream signal.…”

Section: Resultsmentioning

confidence: 96%

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

et al. 2023

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Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin. However, the interactions between curcumin and human SIK3 have not yet been investigated in detail. In this study, we studied the binding models for the interactions between curcumin and human SIK3 using computational tools such as homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations. The open activity loop conformation of SIK3 with the ketoenol form of curcumin was the optimal binding model. The I72, V80, A93, Y144, A145, and L195 residues played a key role for curcumin binding with human SIK3. The interactions between curcumin and human SIK3 were also investigated using the kinase assay. Moreover, curcumin exhibited an IC50 (half-maximal inhibitory concentration) value of 131 nM, and it showed significant antiproliferative activities of 9.62 ± 0.33 µM and 72.37 ± 0.37 µM against the MCF-7 and MDA-MB-23 cell lines, respectively. This study provides detailed information on the binding of curcumin with human SIK3 and may facilitate the design of novel salt-inducible kinases inhibitors.

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Section: Resultsmentioning

confidence: 96%

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

et al. 2023

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“…In addition, the T-loop for protein kinase has diversified conformations, with open, closed, and intermediate conformations. For instance, human FAK may exhibit an open or closed T-loop conformation while binding with FAK inhibitors ( Shi et al, 2022a ; Guo et al, 2022 ). However, some inhibitors, such as the pan-kinase inhibitor bosutinib-bound SIK2, can also bind to the protein kinase with conformational plasticity in the active pocket of the T-loop ( Shi et al, 2022c ).…”

Section: Resultsmentioning

confidence: 99%

“…The root-mean-square fluctuation in the conformation of human CDK6 residues was analyzed based on the frames in the 500 ns simulations. Notably, there were four regions of human CDK6 with significant fluctuations (Figure 2 (Shi et al, 2022a;Guo et al, 2022). However, some inhibitors, such as the pan-kinase inhibitor bosutinib-bound SIK2, can also bind to the protein kinase with conformational plasticity in the active pocket of the T-loop (Shi et al, 2022c).…”

Section: System Stabilitymentioning

confidence: 99%

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

Zhou

Luo

et al. 2023

Front. Pharmacol.

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CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.

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Identification of defactinib derivatives targeting focal adhesion kinase using ensemble docking, molecular dynamics simulations and binding free energy calculations

Cited by 2 publications

References 153 publications

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation

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