Dynamics based pharmacophore models for screening potential inhibitors of mycobacterial cyclopropane synthase

The therapeutic challenges in the treatment of tuberculosis demand multidisciplinary approaches for the identification of potential drug targets as well as fast and accurate techniques to screen huge chemical libraries. Mycobacterial cyclopropane synthase (CmaA1) has been shown to be essential for the survival of the bacteria due to its critical role in the synthesis of mycolic acids. The present study proposes pharmacophore models based on the structure of CmaA1 taking into account its various states in the cyclopropanation process, and their dynamic nature as assessed using molecular dynamics (MD) simulations. The qualities of these pharmacophore models were validated by mapping 23 molecules that have been previously reported to exhibit inhibitory activities on CmaA1. Additionally, 1398 compounds that have been shown to be inactive for tuberculosis were collected from the ChEMBL database and were screened against the models for validation. The models were further validated by comparing the results from pharmacophore mapping with the results obtained from docking these molecules with the respective protein structures. The best models are suggested by validating all the models based on their screening abilities and by comparing with docking results. The models generated from the MD trajectories were found to perform better than the one generated based on the crystal structure demonstrating the importance of incorporating receptor flexibility in drug design.