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Minus 1a5aa4f1c08b567c9107cba729de26bc87c17ab2b2f690eb45059193a1d6f587 Combining Cheminformatics Methods and Pathway Analysis To Identify Molecules With Whole-Cell Activity Against Mycobacterium tuberculosis
Sarker, Malabika and Talcott, Carolyn and Madrid, Peter and Chopra, Sidharth and Bunin, Barry A and Lamichhane, Gyanu and Freundlich, Joel S and Ekins, Sean - 2012 - PDF

Purpose: New strategies for developing inhibitors of Mycobacterium tuberculosis (Mtb) are required in order to identify the next generation of tuberculosis (TB) drugs. Our approach leverages the integration of intensive data mining and curation and computational approaches, including cheminformatics combined with bioinformatics, to suggest biological targets and their small molecule modulators. Methods: We now describe an approach that uses the TBCyc pathway and genome database, the Collaborative Drug Discovery database of molecules with activity against Mtb and their associated targets, a 3D pharmacophore approach and Bayesian models of TB activity in order to select pathways and metabolites and ultimately prioritize molecules that may be acting as metabolite mimics and exhibit activity against TB. Results: In this study we combined the TB cheminformatics and pathways databases that enabled us to computationally search >80,000 vendor available molecules and ultimately test 23 compounds in vitro that resulted in two compounds (N-(2- furylmethyl)-N’-[(5-nitro-3-thienyl)carbonyl]thiourea and N-[(5-nitro-3-thienyl)carbonyl]- N’-(2-thienylmethyl)thiourea) proposed as mimics of D-fructose 1,6 bisphosphate, (MIC N’-(2-thienylmethyl)thiourea) proposed as mimics of D-fructose 1,6 bisphosphate, (MIC of 20 and 40 g/ml, respectively). Conclusion: This is a simple yet novel approach that has the potential to identify inhibitors of bacterial growth as illustrated by compounds identified in this study that have activity against Mtb.