Structure‐based virtual screening toward the discovery of novel inhibitors of the DNA repair activity of the human apurinic/apyrimidinic endonuclease 1 |
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Authors: | Patrícia S Guerreiro Sílvia G Estácio Fernando Antunes Ana S Fernandes Pedro F Pinheiro João G Costa Matilde Castro Joana P Miranda Rita C Guedes Nuno G Oliveira |
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Institution: | 1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal;2. BioISI – Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal;3. Departamento de Química e Bioquímica and Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal;4. CBIOS, Universidade Lusófona Research Center for Biosciences and Health Technologies, Lisbon, Portugal;5. Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal |
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Abstract: | The DNA repair activity of human apurinic/apyrimidinic endonuclease 1 (APE1) has been recognized as a promising target for the development of small‐molecule inhibitors to be used in combination with anticancer agents. In an attempt to identify novel inhibitors of APE1, we present a structure‐based virtual screening (SBVS) study based on molecular docking analysis of the compounds of NCI database using the GOLD 5.1.0 (Genetic Optimization for Ligand Docking) suite of programs. Compounds selected in this screening were tested with a fluorescence‐based APE1 endonuclease activity assay. Two compounds ( 37 and 41 ) were able to inhibit the multifunctional enzyme APE1 in the micromolar range, while compound 22 showed inhibitory effects at nanomolar concentrations. These results were confirmed by a plasmid DNA nicking assay. In addition, the potential APE1 inhibitors did not affect the cell viability of non‐tumor MCF10A cells. Overall, compounds 22 , 37, and 41 appear to be important scaffolds for the design of novel APE1 inhibitors and this study highlights the relevance of in silico‐based approaches as valuable tools in drug discovery. |
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Keywords: | APE1 inhibitors BER pathway cancer DNA damage drug discovery molecular docking virtual screening |
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