Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

Lee, Wendy; Crawford, James J.; Aliagas, Ignacio; Murray, Lesley J.; Tay, Suzanne; Wang, Weiru; Heise, Christopher E.; Hoeflich, Klaus P.; La, Hank; Mathieu, Simon; Mintzer, Robert; Ramaswamy, Sreemathy; Rougé, Lionel; Rudolph, Joachim

doi:10.1016/j.bmcl.2016.06.031

Cited by 14 publications

(7 citation statements)

References 29 publications

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“…Docking results showed similar binding mode for both the compounds. This observation was in accordance with the previous study [11] . As shown in Table 1, most potent compound 8 exhibited higher binding energy of -7.10 kcal/mol as compared to least potent compound 4 which demonstrated binding energy of -5.74 kcal/mol.…”

Section: Resultssupporting

confidence: 94%

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Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

Balupuri¹,

Balasubramanian²,

Cho³

2016

Journal of the Chosun Natural Science

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The p21-activated kinase-1 (PAK1) has emerged as a potential target for anticancer therapy. It is overexpressed in ovarian, breast and bladder cancers. This suggests that PAK1 may contribute to tumorigenesis. 4-azaindole derivatives are reported as potent PAK1 inhibitors. The present work deals with the molecular docking studies of 4-azaindoles with PAK1. Probable binding mode of these inhibitors has been identified by molecular modeling. Docking results indicated that hydrogen bonding interactions with Glu345 and Leu347 are responsible for governing inhibitor potency of the compounds. Additionally, Val284, Val328, Met344 and Leu396 were found to be accountable for hydrophobic interactions inside the active site of PAK1

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Section: Resultssupporting

confidence: 94%

“…Recently, Lee et al reported a series of 4-azaindolecontaining PAK1 inhibitors [11] . The current study is to predict the binding mode of these inhibitors and to explore the binding interaction in the active site of PAK1.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

Balupuri¹,

Balasubramanian²,

Cho³

2016

Journal of the Chosun Natural Science

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show abstract

“…Additionally, some molecules such as selenium-containing ones [ 103 ] were excluded because their topological descriptors, for instance, cannot be enumerated. Those ER values were discarded when they were not consistent with their measured P app (B→A) and P app (A→B) values [ 104 ]. Recently, the efflux ratios of more than 4000 Amgen in-house compounds were measured [ 105 ].…”

Section: Resultsmentioning

confidence: 99%

Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

et al. 2018

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P-glycoprotein (P-gp), a membrane-bound transporter, can eliminate xenobiotics by transporting them out of the cells or blood–brain barrier (BBB) at the expense of ATP hydrolysis. Thus, P-gp mediated efflux plays a pivotal role in altering the absorption and disposition of a wide range of substrates. Nevertheless, the mechanism of P-gp substrate efflux is rather complex since it can take place through active transport and passive permeability in addition to multiple P-gp substrate binding sites. A nonlinear quantitative structure–activity relationship (QSAR) model was developed in this study using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to explore the perplexing relationships between descriptors and efflux ratio. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 50, r2 = 0.96, qCV2 = 0.94, RMSE = 0.10, s = 0.10) and test set (n = 13, q2 = 0.80–0.87, RMSE = 0.21, s = 0.22). When subjected to a variety of statistical validations, the developed HSVR model consistently met the most stringent criteria. A mock test also asserted the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.

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“…Additionally, some molecules such as those seleniumcontaining ones [137] were excluded due to the fact that their topological descriptors, for instance, cannot be enumerated. Those ER values were discarded when they were not consistent with their measured Papp (B→A) and Papp (A→B) values [138]. Recently, the efflux ratios of more than 4,000…”

Section: F2mentioning

confidence: 99%

Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

Chen

Lee

Weng

et al. 2018

Preprint

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P-glycoprotein (P-gp), a membrane-bound transporter, can eliminate xenobiotics by transporting them out of the cells or blood-brain barrier (BBB) at the expense of ATP hydrolysis. Thus, P-gp mediated efflux plays a pivotal role in altering the absorption and disposition of a wide range of substrates. Nevertheless, the mechanism of P-gp substrate efflux is rather complex since it can take place through active transport and passive permeability in addition to multiple P-gp substrate binding sites. A nonlinear quantitative structure-activity relationship (QSAR) model was developed in this study using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to explore the perplexing relationships between descriptors and efflux ratio. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 50, r2 = 0.96, q2CV = 0.94, RMSE = 0.10, s = 0.10) and test set (n = 13, q2 = 0.80–0.87, RMSE = 0.21, s = 0.22). When subjected to a variety of statistical validations, the developed HSVR model consistently met the most stringent criteria. A mock test also asserted the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.

show abstract

Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

Cited by 14 publications

References 29 publications

Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

Molecular Docking Studies of p21-Activated Kinase-1 (PAK1) Inhibitors

Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

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