The aim of the Project is to develop the computational protocol and its application to the search of new lead structures for ligands of the serotonin receptor 5-HT7 with improved metabolic stability, the extremely important parameter in the campaigns oriented towards new drugs development. The comprehensive protocol for the in silico evaluation of compounds will include both the tools for the activity towards 5-HT7R evaluation and (as a result of deep theoretical investigations) there will be developed methods enabling the assessment of the metabolic stability of compounds. The selected compounds will be purchased from the commercial vendors and their activity and metabolic stability will be verified in the in vitro experiments. The series of derivatives of compounds with the most promising activity-metabolic stability profile will be synthetized.
The evaluation of compounds will be performed for the two types of structures libraries – the sets of compounds commercially available and the sets of compounds generated in a combinatorial way (scaffold‑hopping, bioisosteric replacement, hybdridization of known ligands). The activity evaluation will be performed automatically, both in the ligand- and in the structure-based approaches with the machine learning methods as the core of the applied methodologies, with the use of various representations of compounds and ligand-receptor complexes obtained from docking and data fusion methods for the final activity prediction. The tools for the metabolic stability evaluation will also be based on machine learning – both classification and regression approaches will be applied and, similarly to the activity evaluation, the assessment will be based solely on the structures and properties of compounds with already examined metabolic stability (ligand-based approach), as well as the metabolic stability evaluation will be performed on the basis of the results of docking to the selected CYP 450 isoforms followed by the automatic evaluation of docking results with the use of the structural interaction fingerprint and machine learning methods. Compounds with the most promising activity and metabolic stability properties will be purchased and their 5-HT7R affinity will be verified in radioligand binding experiments. For compounds with confirmed 5-HT7R activity, the metabolic stability tests will be performed in vitro. The most active and stable compounds will constitute an input for the generation of the next series of combinatorial libraries, and also their derivatives will be synthetized, to enable performing the detailed analysis of the structure-activity and structure-metabolic stability relationships analyses.
Research project impact
The wide occurrence of the 5-HT7R, and their remarkable role that they play in the organism hand, as well as the limitations of already existing drugs targeting this receptor are an impulse for the search of new groups of compounds with the ability to modulate the activity of this receptor. On the other hand, despite the desired receptor affinity, it is also extremely important to pay attention on physicochemical and pharmacokinetic properties, including the metabolic stability. Finding of new lead structures for the 5-HT7R with preferential metabolic stability properties in the long-term perspective can contribute to the development of new drugs acting within the central nervous system, enabling the therapy of crucial disorders from the social point of view, such as depression, cognitive disorders and Alzheimer disease. Moreover, the Project will bring significant knowledge both in the field of structural requirements for the 5-HT7R ligands, as well as the structure-metabolic stability relationships.
The presented Project will be implemented in cooperation with the Faculty of Pharmacy University of Bari (the group of Prof. Marcello Leopoldo). The Foreign Partner is deeply experienced both in carrying out the experimental tests for metabolic stability and also in the development of compounds with improved metabolic stability properties, and synthesis of the 5-HT7R ligands. Therefore, the main role of the Prof. Leopoldo’s group will be the experimental validation of the metabolic stability of the selected compounds and the synthesis of derivatives of the compounds characterized by high activity towards 5‑HT7R and high metabolic stability at the same time; however, the Foreign Partner will also be involved in the remaining Project tasks, during the whole period of the Project implementation. The experience and knowledge of the prof. Leopoldo’s group both in the field of metabolic stability as well as in the field of 5‑HT7R ligands being the main subject of the Project will definitely help in the successful Project implementation and the strengthening of the cooperation between the two institutions participating in the Project (IP PAS/University of Bari).
Rafał Kafel, MSc
phone: +4812 66 23 301
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