Molecular modeling of peptide deformylase and structure-based pharmacophore screening for inhibitors

• Published in: RSC advances 2016-03, Vol.6 (35), p.29466-29485
• Main Authors: Manhas, Anu, Kumar, Sivakumar Prasanth, Jha, Prakash Chandra
• Format: Article
• ISSN: 2046-2069
• DOI: 10.1039/c6ra01071g

Plasmodium falciparum peptide deformylase ( Pf PDF), a metalloenzyme which catalytically removes the N-formyl group from N-terminal methionine from polypeptide during protein maturation, is a potential drug target for antimalarial drug design but is less explored in comparison to its bacterial counterpart due to difficulties in enzyme purification, the labile nature of the metal cofactors, and the absence of crystal data of the enzyme-inhibitor complex and inhibitors. We used molecular modeling techniques to study the effect of different metal ions, Co 2+ , Zn 2+ , Ni 2+ and Fe 2+ towards actinonin binding and recognized Pf PDF-Co 2+ -actinonin inhibitor complex as the energetically favorable structure supported by biochemical characterizations. Further, we analyzed the favorable coordination geometry of bound metal cofactor and showed that its geometry did not affect the binding mode of actinonin consistent with the crystallographic observations which suggested that FlexX docking-based virtual screening may be effectively applied to recognize Pf PDF binders. Structure-based pharmacophore screening of Pf PDF-Co 2+ -actinonin complex recognized five potential hits and analyzed their effectiveness in chelating metal cofactor and ability to develop similar poses in both pharmacophore fit and docking. From the geometrical properties and characteristics of antibacterial PDF inhibitors, CAP01891052 (a triazine and quinoline containing molecule) and IBS297042 (an indole and piperidine containing molecule) were prioritized as promising lead molecules to modulate Pf PDF activity. The role of metal coordination geometry and actinonin (inhibitor) binding was examined to develop pharmacophore-based inhibitor design strategy for Plasmodium falciparum peptide deformylase.