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Title: Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design
Authors: Guedes, Romina A. 
Aniceto, Natália
Andrade, Marina A. P.
Salvador, Jorge A. R. 
Guedes, Rita C.
Keywords: proteasome; proteasome inhibitors; molecular descriptors; fingerprints; chemical space; decision tree; structure-activity relationship
Issue Date: 25-Oct-2019
Publisher: MDPI
Project: This study was supported by the Portuguese science foundation FCT (Fundação para a Ciência e a Tecnologia, Portugal) through the research projects PTDC/QEQ-MED/7042/2014, UID/DTP/04138/2019 and the PhD grant SFRH/BD/104441/2014 (R.A.G.), being also supported by the European Structural & Investment Funds through the COMPETE Programme under grant LISBOA-01-0145-FEDER-016405 (SAICTPAC/0019/2015). J.A.R.S. thanks PT2020 (Programa Operacional do Centro 2020), and the financial support by FEDER (European Regional Development Fund) through the COMPETE 2020 Programme (Operational Programme for Competitiveness and Internationalization), project CENTRO-01-0247-FEDER-003269, drugs2CAD. 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 20
Issue: 21
Abstract: Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that multiple compounds have been designed and tested for the last 20 years, and this collection of data is yet to be subjected to such type of assessment. This study presents a retrospective overview of two decades of proteasome inhibitors development (680 compounds), in order to gather what could be learned from them and apply this knowledge to any future drug discovery on this subject. Our analysis focused on how different chemical descriptors coupled with statistical tools can be used to extract interesting patterns of activity. Multiple instances of the structure-activity relationship were observed in this dataset, either for isolated molecular descriptors (e.g., molecular refractivity and topological polar surface area) as well as scaffold similarity or chemical space overlap. Building a decision tree allowed the identification of two meaningful decision rules that describe the chemical parameters associated with high activity. Additionally, a characterization of the prevalence of key functional groups gives insight into global patterns followed in drug discovery projects, and highlights some systematically underexplored parts of the chemical space. The various chemical patterns identified provided useful insight that can be applied in future drug discovery projects, and give an overview of what has been done so far.
ISSN: 1422-0067
DOI: 10.3390/ijms20215326
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais

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