SN2DNA · In silico design and assessment of novel polyelectrophylic chemotherapy agents
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-06-01 → 2024-05-31
- EU contribution
- €259,399
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
In silico design and assessment of novel polyelectrophylic chemotherapy agents
DNA-damaging agents remain one of the most important chemotherapeutic strategies for the treatment of cancer(1). The drugs designed for this purpose generally contain two leaving groups that, by means SN2 reactions, form cross-linking DNA complexes of type (1,2)-intrastrand, (1,3)-intrastrand or (1,2’)-interstrand. In this kind of chemical transformations, the nucleophile (Nu:)—a DNA base, in most cases guanine (G) and, into a lesser extent, adenine (A)—attacks the chemotherapeutic reagent, which acts as an electrophile, to release a leaving group (Lg). Thus, assuming Nu:= G and Lg = Cl, the general reaction is DNA-G + E-Cl → DNA-G(+)-E+ Cl(-) (Figure 1). Although this reaction implicates in serious harm to the double-helix structure those damages can be reversed by repair pathways in cancer cells, thus limiting the therapeutic success of these reagents, especially in further rounds of chemotherapy(2). To address this issue, platinum-based compounds, named Aurkine, were synthetized, based on increasing the number of electrophilic positions (En), that must generate interstrand crosslink adducts that should result in irreversible lesions in the DNA of cancer cells. Within this context, we have applied computational chemistry methods based on Quantum Mechanics (QM) and Molecular Dynamics (MD), for a better understanding how those compounds compromise the structure of a DNA sequence. These studies have given us insights on the structural distortions induced by these drug candidates as well as to predict the kinetics of these processes via successive SN2 reactions on guanine residues.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNIVERSIDAD DEL PAIS VASCO/ EUSKAL HERRIKO UNIBERTSITATEA · LeioaCoordinatorSpain
Links
Data: CORDIS, © European Union