A computationally assisted drug development pipeline for challenging cancers with very few effective therapeutic options

PI Daniel dos Santos

Co-PI Maria José U. Ferreira

From 2024 – present

Description

This HPC project corresponds to the second part of the computational working package of the project 2022.05718.PTDC, already approved by FCT (“Exploiting monoterpene indole alkaloid derivatives for overcoming resistance in BRCA-deficient cancers. In silico characterization of binding modes”).

The group of Prof. Maria J.U Ferreira (Co-PI; imed/FFUL) identified a monoterpene indole alkaloid derivative (BBIT20) with the ability to target homologous recombination DNA repair defects by disrupting the BRCA1-BARD1 heterodimer in triple-negative breast and ovarian cancer cells. The BRCA1 and BARD1 proteins, both involved in homologous recombination, have been associated with altered DNA repair mechanisms in several different types of cancer, such as pancreatic tumors, advanced ovarian and triple-negative breast cancer. BBIT20 showed promising in vitro and in vivo antitumor activity while in synergistic interaction with PARP inhibitor Olaparib and cisplatin. BBIT20 is patented and is the first reported disrupter of the BRCA1-BARD1 complex and may be a strong starting point for the continued development of new anticancer agents against the harder to treat cancers with very few effective therapeutic options.

The goals of this project are to find the BBIT20’s binding mode and thereafter allow the guided development of new effective plant-derived alkaloids capable of reversing drug resistance in cancer cells, through disruption of the BRCA1-BARD1 complex. BBIT20’s binding mode will be characterized through computational approaches. The binding hot spots were already identified by molecular docking in the first part of the running FCT project. Now, in this HPC project, molecular dynamics will help understand the type of interaction and mode of action. A rational for the molecular derivatization of compounds for the phytochemical studies will be established, that will help to clarify structure-activity trends and the design of novel analogs with improved binding capability.

Funding

FCT, Advanced Computing Project, reference 2023.10598.CPCA.A2