Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC of Leptospira spp.: homology modeling, docking, and molecular dynamics study

Abstract

Leptospira interrogans, a Gram-negative bacterial pathogen is the main cause of human leptospirosis. Lipid A is a highly immunoreactive endotoxic center of lipopolysaccharide (LPS) that anchors LPS into the outer membrane of Leptospira. Discovery of compounds inhibiting lipid-A biosynthetic pathway would be promising for dissolving the structural integrity of membrane leading to cell lysis and death of Leptospira. LpxC, a unique enzyme of lipid-A biosynthetic pathway was identified as common drug target of Leptospira. Herein, homology modeling, docking, and molecular dynamics (MD) simulations were employed to discover potential inhibitors of LpxC. A reliable tertiary structure of LpxC in complex with inhibitor BB-78485 was constructed in Modeller 9v8. A data-set of BB-78485 structural analogs were docked with LpxC in Maestro v9.2 virtual screening workflow, which implements three stage Glide docking protocol. Twelve lead molecules with better XP Gscore compared to BB-78485 were proposed as potential inhibitors of LpxC. Para-(benzoyl)-phenylalanine – that showed lowest XP Gscore (−10.35 kcal/mol) – was predicted to have best binding affinity towards LpxC. MD simulations were performed for LpxC and para-(benzoyl)-phenylalanine docking complex in Desmond v3.0. Trajectory analysis showed the docking complex and inter-molecular interactions was stable throughout the entire production part of MD simulations. The results indicate para-(benzoyl)-phenylalanine as a potent drug molecule against leptospirosis.

An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:10

Keywords:

• Leptospirosis
• lipopolysaccharide (LPS) biosynthesis
• para-(benzoyl)-phenylalanine
• virtual screening
• docking
• molecular dynamics (MD) simulations

Acknowledgments

Authors are highly thankful to DBT, Ministry of Science and Technology, Govt. of India for supporting research at SVIMS Bioinformatics center. We are also thankful to Dr. B. Vengamma, Director, SVIMS for her constant encouragement and support.