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SCIGRESS - Case Studies - High Throughput Modeling of Efflux Lability of Putative Antibiotic Scaffolds

BioSciences Group, Fujitsu


Calculations done using CAChe


Efflux via multidrug resistant transporters (MDRTs) is a major factor in determining antibiotic resistance in antibiotic resistant microorganisms (ARMs) and Multi-drug resistant strains (MDRS) of microorganisms. In addition, MDRTs have been implicated in expression of chemi-resistance in cancer cells. In developing novel antibiotics, the ability to model the likely interaction with MDRTs would be a crucial time saving step. However, there exist limited high resolution crystal structures of MDRTs within the public sector (i.e., www.pdb.org).

Utilizing a desktop installation of Scigress Explorer (BioMedCAChe) with the Active Site module, pdb files for 3 MDRTs (1PF4, 1JSQ and 1S7B) and publicly available bioinformatics algorithms (CLUSTAL W and pFAM), researchers were able to develop a consensus homology model for the active site of MDRTs expressed in both drug resistant strains of E. coli and Vibrio cholerae. The model was used to screen a small library (200 compounds) of antibiotic lead compounds provided by a commercial collaborator. Each of the compounds exhibited similar IC50s based on in vitro binding studies against the drug target yet showed divergence in MIC50 activities when tested against genomovars of drug resistant strains.

A prioritized lead set of 12 compounds with minimal interaction with the binding site in any conformation was identified and a significant QSAR relationship between compound structure, binding interaction with MDRT and biological activity was elucidated.



Ian G. Welsford, Ph.D. Fujitsu Computer Systems, BioSciences Group

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