Pharmacophore modeling and structure-based virtual screening for a novel “switch region” target of bacterial RNA polymerase

摘要

RNA polymerase (RNAP), an essential enzyme involved in the DNA transcription pathway, has been suggested as an attractive target for treating tuberculosis. The novel “switch region” active site has been validated and the high-resolution crystallographic structure of the inhibitor–RNAP complexes has been produced. And virtual screening target “switch region” has been performed. We proposed pharmacophore model which based on the crystallographic structure and a new combination of three docking procedures (Surflex-Dock, Gold, and AutoDock) to increase enrichment. The virtual screening protocol combined 3D pharmacophore filtering, Lipinski’s rule of 5, docking and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder-Myx. The virtual screen resulted in the selection of 27 compounds that were acquired from 321, 374 starting structures. This is the first example of virtual screening which target “switch region” of RNAP.