Computational design and screening of novel dipeptide analogues as potent antileprotic agents against alanine racemase and ligase

Mycobacterium Leprae is the root cause of the granulomatous skin condition known as leprosy. This causes the development of cutaneous lesions in the skin. Transmission primarily occurs through coughing or exposure to respiratory droplets, resulting in cutaneous lesions. Leprosy is a common mycobacterial disease caused by Mycobacterium leprae, which necessitates the investigation of innovative therapeutic agents that can inhibit essential enzymes involved in cell wall synthesis. This study aimed to assess various dipeptides and tripeptides as potential inhibitors of alanine ligase and alanine racemase, two enzymes critical for cell wall genesis in Mycobacterium leprae. Molecular docking analyses were conducted using Swiss DOCK for alanine racemase (PDB ID 1BDO) and alanine ligase (PDB ID 3LWB). Discovery Studio Visualizer and Chimera software were used to analyze and interpret the three-dimensional interactions of peptide ligands with the target enzyme. A total of 19 dipeptide and tripeptide compounds were assessed based on their binding affinity values. Leu-Glu-Leu demonstrated the highest binding affinity toward alanine racemase, with a binding energy of −8.61 kcal/mole. Glu-Leu-Met was identified as the most effective inhibitor of alanine ligase, with a binding energy of −8.34 kcal/mol. These results were superior to those of the standard drugs Dapsone and Clofazimine, which showed comparatively lower binding affinity values for both enzymes. Leu-Glu-Leu and Glu-Leu-Met exhibited strong inhibitory potential against alanine racemase and alanine ligase, respectively, suggesting that short-chain peptides may serve as promising therapeutic candidates for leprosy treatment. The graphical abstract represents the methodology used to develop the potential antileprotic agents.