Unleashing the unstructured proteins as potential drug target: A case study on Mycobacterium Tuberculosis

Meenakshi Anurag, Namit Bharija, Saurabh V Laddha, Debasis Dash
G.N. Ramachandran Knowledge Centre for Genome Informatics, Institute of Genomics and Integrative Biology, CSIR, 254, Okhla phase III, New Delhi, India

Intrinsically unstructured proteins (IUPs) occur across all kingdoms of life. Such proteins are capable of acquiring a dynamic ensemble of structures, in contrast to their structural counterparts. With very little attained so far with structure based rational drug discovery approaches, disrupting protein-protein interactions involving disordered proteins is being considered vital for drug targeting. Our study on Mycobacterium tuberculosis H37Rv strain reveals that seven percent of the proteome comprises of IUPs. Studying further for essentiality, homology with known structures in PDB and lack of homology with human proteome led us to 41 proteins. On the basis of druggability, coupled with structural bioinformatics, pathway analyses and protein-protein interaction studies, we identified a set of proteins that include PknG, CtpH, RocA, FtsW, AroF, RpoB. Tracking down to PknG - Serine/Threonine Kinase and AroF - a probable chorismate synthase that has been labeled as attractive drug targets against the 'Neglected Disease', ascertains our methodology. Our other remarkable finding is a FtsW-like membrane protein belonging to SEDS family, stabilizes the cytokinetic ring of FtsZ - another highly studied target. FtsW is a late recruit in the divisome assembly pathway and hires Penicillin-binding protein (PbpB) for the peptidoglycan synthesis can be foreseen as crucial target to crack the pathogen. A detailed insight of the structural, functional and interactive aspect of these proteins is being studied that would enable us delineate these as potential drug targets.