Para-(benzoyl)-phenylalanine as a potential inhibitor against leptospirosis

Abstract

AbstractLeptospirosis is a zoonotic disease of global concern caused by Leptospira interrogans. Subtractive genomic approach, metabolic pathway analysis and multi strain genome comparisons of Leptospira interrogans serovars had proposed 88 common drug targets from 5,124 genes of serovar Copenhageni and 4,727 genes of serovar Lai. Three potential drug targets (lpxC, lpxD and lpxB) were identified from Lipid A biosynthesis process of lipopolysaccharide (LPS) biosynthesis pathway. Lipid A is one of the three components of LPS that contains multiple hydrophobic fatty acid chains which anchor the LPS into the bacterial membrane. Designing inhibitory drug molecules targeting Lipid A biosynthesis would dissolve the structural integrity of membrane structure leading to cell lysis and death of Leptospira. LpxC being the first enzyme among the three drug targets of Lipid A biosynthesis pathway; blocking the enzyme with suitable inhibitor would stop synthesizing substrates for lpxD and lpxB. Also, there is no alternative mechanism in Leptospira to replace the catalytic activity rendered by lpxC; hence, the drug target was selected herein for rational drug design. The lpxC tertiary structure was modeled incorporating inhibitor BB-78485 using Modeller9v8. The lpxC 3D structure reliability was assessed through various model validation techniques. Ligand based virtual screening was performed from one million entries of ligand.Info metadatabase. The leads were ranked using computational docking technique of Glidev5.5. Twelve leads with better binding affinity than BB-78485 (XPGscore -7.98 Kcal/mol) were proposed as potential inhibitors of lpxC. Para-(benzoyl)-phenylalanine, the best ranked inhibitor (XPGscore -10.34Kcal/mol), would be intriguing for rational drug design against leptospirosis.