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Article

Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB

1
Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d’Orléans 7311, Université d’Orléans BP 6759, 45067 Orléans CEDEX 2, France
2
Janssen-Cilag, Centre de Recherche Pharma, CS10615-Chaussée du Vexin, 27106 Val-de-Reuil, France
*
Author to whom correspondence should be addressed.
Academic Editor: Christian Peifer
Molecules 2020, 25(14), 3226; https://doi.org/10.3390/molecules25143226
Received: 17 June 2020 / Revised: 9 July 2020 / Accepted: 10 July 2020 / Published: 15 July 2020
(This article belongs to the Special Issue Kinase Inhibitors II)
Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of “flatland”, we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb. View Full-Text
Keywords: protein kinase inhibitors; clinical trials; approved drugs; database; chemometrics analysis; kinome; molecular scaffolds; rings system protein kinase inhibitors; clinical trials; approved drugs; database; chemometrics analysis; kinome; molecular scaffolds; rings system
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MDPI and ACS Style

Bournez, C.; Carles, F.; Peyrat, G.; Aci-Sèche, S.; Bourg, S.; Meyer, C.; Bonnet, P. Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB. Molecules 2020, 25, 3226. https://doi.org/10.3390/molecules25143226

AMA Style

Bournez C, Carles F, Peyrat G, Aci-Sèche S, Bourg S, Meyer C, Bonnet P. Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB. Molecules. 2020; 25(14):3226. https://doi.org/10.3390/molecules25143226

Chicago/Turabian Style

Bournez, Colin, Fabrice Carles, Gautier Peyrat, Samia Aci-Sèche, Stéphane Bourg, Christophe Meyer, and Pascal Bonnet. 2020. "Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB" Molecules 25, no. 14: 3226. https://doi.org/10.3390/molecules25143226

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