Record #241528 - GSI Repository

SN2DNA

In silico design and assessment of novel polyelectrophylic chemotherapy agents

Grant period	2021-06-01 - 2024-05-31
Funding body	European Union
Call number	H2020-MSCA-IF-2020
Grant number	101026616
Identifier	G:(EU-Grant)101026616

Note: Administration of DNA-damaging reagents constitutes one of the most effective chemotherapeutic strategies for the cancer treatment. The families of drugs developed over the years for this purpose are based on second-order nucleophilic substitution (SN2) reactions. Innovative candidates to improve the therapeutic action of these compounds have been designed based on increasing the number of electrophilic positions (En) of the reagent by making n>2. This increased electrophilicity must generate interstrand crosslink adducts that should result in irreversible lesions in the DNA of cancer cells. Computational chemistry tools based on quantum mechanics and molecular modelling, constitute key tools for a better understanding of DNA damage and repair after the formation of the covalently bound complexes that distort the double helix. Thus, the aim of the project described in this proposal is to: 1) compute the structures and evaluate the distorting effects of DNA adducts with polyelectrophilic chemotherapeutic reagents, 2) compute the kinetics of the consecutive SN2 processes (on both carbon atoms and metallic centres) involving interstrand and intrastrand crosslinks and 3) assess in silico the ADME (Adsorption, Distribution, Metabolism and Excretion) properties of the synthesised candidates. Those objectives will be achieved by computing the behaviour of different families of molecules through quantum mechanical - at DFT level of theory- and Molecular Mechanics calculations - based on QM/MM method. Some of these candidates have been synthesised in the laboratories of the hosting group and the corresponding preliminary and promising biological results are already available. The outputs of this project will result in a patent proposal and research articles to be published in high impact journals. Our findings will be open-access available in order to contribute with the research on anticancer drugs design.

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Record created 2021-10-10, last modified 2023-02-14

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