This project represents a piece of a wider long-term research aimed at the identification of the most probable molecular targets of a set of natural substances showing pharmacological potential within the recurrent medulloblastoma, a malignant pediatric brain tumor. Initially the main focus will be given to Curcumin that has been shown to have anti-proliferative effects on multiple cancers through targeting several pathways involved in tumorigenesis. The main goal of this part of the work will be the identification of the Curcumin targets in the inhibition of cell proliferation. To this purpose, the docking-based inverse virtual screening technique will be adopted. In this technology, a molecular docking process is employed to screen a protein database for a query ligand, and then to select an enriched subset containing possible targets of the ligand.
This specific part of the project is aimed at the development of an in-house pipeline implementing a strategy using free academic software and the computational power available at Sapienza (TeraStat). Docking engines will be AutoDock and AutoDock Vina, well known and tested free-software produced in the academic context. A Python envelope will be written to run docking experiments in batch and to automatize as far as possible the entire procedure. After the set up and testing of the pipeline, the flow of the project will consists of these steps: 1) selection from the Protein Data Bank of a set of potential Curcumin targets; 2) application of the in-house pipeline; 3) scrutiny and detailed analysis of the results and prioritization of the targets. The project will take advantage from the collaboration with other two units providing expertise in software development and in theoretical simulation of biological molecular systems, and in molecular pathology and cellular biotechnology, respectively. Once tested, the procedure will be applied to probe a number of natural substances on a wider ensemble of potential targets.
This project represents a piece of a more extended long-term research aimed at the identification of the most probable cellular targets of a number of natural substances possessing pharmacological potential. The cellular targets are those involved in the recurrent medulloblastoma, a lethal pediatric neoplasy.
From the technical side, the main purpose of this part of the work is the development of a in-house pipeline implementing an inverse virtual screening strategy using free academic software and the computational power available at Sapienza (TeraStat). Despite much work has been already done in the field, de facto, a universal tool applicable to different problems and systems does not exists yet. From this consideration stems the motivation for the development of a in-house tailored tool. Even if the pipeline will be developed for the specific case, we do not exclude that in the future it may be generalized so to become able to deal with other molecular systems. The possibility to implement the pipeline in a so-called plugin (a piece of software to be included in another program to expand its functions) to be installed in the widely used academic programs for molecular graphics and modelling such as PyMOL and Chimera, will be taken into consideration. We also foresee to include in a few years this pipeline and/or plugin as a Sapienza resource within the Elixir initiative. Sapienza is indeed member of this network.
As for the biomedical context, once the pipeline will be ready and tested, it will be applied to the specific problem: initially, only Curcumin will be tested. We expect to find the most likely molecular targets of this natural compound. The findings will be experimentally tested in vitro by one of the component units (vide infra). The results of the inverse virtual screening will also suggest the most significant interactions taking place between Curcumin and its receptors at the binding site. This may pave the way to the design of chemically modified forms of Curcumin possessing enhanced biological activity and specificity.
Once the pipeline will be fully tested, it will be applied to a set of different natural molecules deemed to possess biological activity against the recurrent medulloblastoma with the hope to find potential candidate to the development of safe anticancer drugs.
In conclusion, this research has the potential to contribute to the development of more handy inverse virtual screening tools and to suggests possible molecular targets for chemically modified forms of natural substances with enhanced biological activity to combat against the recurrent medulloblastoma.