With our consortium we will set up an enabling platform to facilitate drug repurposing, molecular mode of action (MMOA) determination of drugs and the design of polypharmacological and drug-cocktailing- based strategies. This platform combines in-house phenotypic and molecular characterization with advanced datamining and bioinformatics approaches.
Concretely our platform consists of
Enabling technology to construct drug-target networks using public data on approved drug-target interactions and their chemical/structural properties in the chemical and genomics space. (WP1)
Enabling technology to construct molecular interaction networks on the organism of interest from publicly available omics data. (WP2)
Enabling technology to interrogate molecular interaction networks with in-house generated data to determine the mode of action of drugs. (WP2)
An advanced analytical platform for testing the phenotypic and molecular effect of anti-biofilm agents. (WP3)
To proof the added value of our network-based strategy (1-3) we will apply it to the development of anti- biofilm agents of Salmonella, E. coli and P. aeruginosa (WP4&5). Screening several types of compound libraries (both repurposed drugs as well as other types of compounds) for anti-biofilm activity with the advanced phenotypic screening/characterization platform will result in anti-biofilm agents that (i) specifically target biofilms; (ii) have reduced resistance development by selecting for anti-biofilm agents that affect multiple targets; (iii) their anti-bacterial activity spectrum being determined; (iv) their activity spectrum under different environmental conditions being determined (v) with facilitated registration through drug repurposing. To facilitate transfer of the novel anti-biofilm compounds to companies in Flanders, valorization-oriented challenge tests (WP6) will be performed during the project for a number of application types, preferentially in collaboration with companies of the user committee. To prove the genericity of the enabling platform, we will apply it to a second case focusing on therapeutics against a human disease, under development in the Centre for Drug Design and Discovery(CD3) (WP7).
In order to achieve this we set up an interdisciplinary research consortium with complementary expertises in the development of antimicrobials (CMPG-KU Leuven), in drug development (CD3-KU Leuven), QSAR and chemogenomics (BIOMOL-KU Leuven and DTAI-KU Leuven) and computational systems biology (N2N- UGent)
With this strategy, NEMOA envisages an innovative way of addressing problems related to the increasing cost and complexity of drug development:
It offers a platform for drug repurposing by maximally exploiting publicly available knowledge.
By combining a strategy based on phenotypic characterization with a simultaneous MMOA determination, it combines the advantages of a target-based strategy that starts from the MMOA with the efficacy of a phenotypic screening.
Providing insight in the MMOA at global cellular level (interference of the drug with signaling and reaction pathways) and not only at a the level of the local interaction between the drug and its target will aid in the design of more complex therapeutics (drug-cocktailing, polypharmacology) that can overcome problems related to multiple resistance.