Computational Approaches to Identify a Derivative of Galardin as an Inhibitor of Mycobacterial Peptide Deformylase

Abstract

Abstract. The metalloenzyme peptide deformylase (PDF) catalyzes the elimination of the N-formyl group from N-terminal methionine upon translation, which is crucial for protein synthesis, growth, and survival of bacteria. In this context, we aim to identify potent derivatives of the known mycobacterial PDF (mPDF) inhibitors having better pharmacological properties than their parent compounds. Initially, BB-83698, Galardin, and LBK-611 known mPDF inhibitors were selected based on their binding affinity for mPDF using iGEMDOCK. Analogs of these three inhibitors were prepared. Further, the analogs were screened based on their oral bioavailability, pharmacokinetics properties, drug likeliness and binding energy. The post-screening analysis reveals that the analog, (2R)-N’-hydroxy-N-[(2S)-3-(5H-indol-3-yl)-1-oxopropan-2-yl]-2-(2-methylpropyl) butanediamide (CID5288446) of galardin interacts with residues GLN56, LEU107, HIS148, GLU149, and HIS152 near the vicinity of the active site (H¹³²EXXH¹³⁶) of mPDF protein with higher affinity as compared to its parent compound galardin. The prediction tool based upon structure-activity relationship reveals that the analog CID5288446 showed similar metalloproteinase activity with lesser toxic effects when compared to its parent compound galardin.

Keywords: Mycobacterial Peptide Deformylase (mPDF); structure-based virtual screening; fitness score; pharmacokinetics properties; drug likeliness; Inhibitors.