ChemInform Abstract: Design Strategies, Structure Activity Relationship and Mechanistic Insights for Purines as Kinase Inhibitors

Abstract The compound optimization monitor (COMO) approach was originally developed as a diagnostic approach to aid in evaluating development stages of analog series and progress made during lead optimization. COMO uses virtual analog populations for the assessment of chemical saturation of analog series and has been further developed to bridge between optimization diagnostics and compound design. Herein, we discuss key methodological features of COMO in its scientific context and present a deep learning extension of COMO for generative molecular design, leading to the introduction of DeepCOMO. Applications on exemplary analog series are reported to illustrate the entire DeepCOMO repertoire, ranging from chemical saturation and structure–activity relationship progression diagnostics to the evaluation of different analog design strategies and prioritization of virtual candidates for optimization efforts, taking into account the development stage of individual analog series.

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Structure-activity relationship of 7-aryl-2-anilino-pyrrolopyrimidines as Mer and Axl tyrosine kinase inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2020.1825407 ◽

2020 ◽

Vol 35 (1) ◽

pp. 1822-1833

Author(s):

Shin Hyuck Chung ◽

Jiwon Park ◽

Jung Wuk Lee ◽

Jiho Song ◽

Danbee Jung ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Relationship Of

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Identification and structure–activity relationship of 2-morpholino 6-(3-hydroxyphenyl) pyrimidines, a class of potent and selective PI3 kinase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2010.10.021 ◽

2010 ◽

Vol 20 (23) ◽

pp. 6895-6898 ◽

Cited By ~ 21

Author(s):

Sabina Pecchi ◽

Paul A. Renhowe ◽

Clarke Taylor ◽

Susan Kaufman ◽

Hanne Merritt ◽

...

Keyword(s):

Kinase Inhibitors ◽

Structure Activity Relationship ◽

Pi3 Kinase ◽

Activity Relationship ◽

Structure Activity ◽

Relationship Of

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Quantitative Structure-Activity Relationship Studies for Potential Rho-Associated Protein Kinase Inhibitors

Journal of Chemistry ◽

10.1155/2016/9198582 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Giovanna Cardoso Gajo ◽

Tamiris Maria de Assis ◽

Letícia Cristina Assis ◽

Teodorico Castro Ramalho ◽

Elaine Fontes Ferreira da Cunha

Keyword(s):

Protein Kinase ◽

Kinase Inhibitors ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Protein Kinase Inhibitors ◽

Activity Relationship ◽

Quantitative Structure ◽

Qsar Analysis ◽

Structure Activity ◽

New Compounds

A series of pyridylthiazole derivatives developed by Lawrence et al. as Rho-associated protein kinase inhibitors were subjected to four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. The models were generated applying genetic algorithm (GA) optimization combined with partial least squares (PLS) regression. The best model presented validation values ofr2=0.773,qCV2=0.672,rpred2=0.503,Δrm2=0.197,rm test2⁡⁡=0.520,rY-rand2=0.19, andRp2=0.590. Furthermore, analyzing the descriptors it was possible to propose new compounds that predicted higher inhibitory concentration values than the most active compound of the series.

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