Imidazole is an important class of heterocyclic compounds exhibiting a diverse biological and pharmacological functions. Despite the growing understanding of the structure of MPO and its enzymatic functions, few therapeutically suitable inhibitors which specifically target MPO have been discovered (Lazarevic-Pasti et al., 2015). Few compounds have been investigated for their property of inhibiting MPO enzyme, like, Hydroxamic acids (Davies and Edwards, 1989), Benzoic acid Hydrazides (Ator et al., 1987), Indoles (Hallingbäck et al., 2006), Tryptamines (Kettle and Candaeis, 2000), and natural products like flavonoids (Kawai et al., 2006 Momić et al., 2008) and resveratrol (Kohnen et al., 2007). There are numerous studies being done to tackle the negative effect of the MPO enzyme activity by scavenging the reactive products of MPO activity (Shiba et al., 2008) or by directly inhibiting the target enzyme (Galijasevic et al., 2008 Kettle et al., 1995).
It is therefore necessary to modulate the production of HOCl by inhibiting the MPO enzyme. However, under pathological conditions, increased activation of MPO-H 2O 2 system can cause tissue damage of the host due to access amount of hypochlorous acid (Hawkins, 2020 Krasowska and Konat, 2004 Souza et al., 2011 Ulfig and Leichert, 2021). Electrochemical sensor has been devised for fast and simple detection of wound infection based on Myeloperoxidase activity as an indication for inflammation (Hajnsek et al., 2015). Inflammation and oxidative stress are related to the activity of MPO enzyme which catalyzes the production of potent antimicrobial oxidant hypochlorous acid from H 2O 2 and halides (particularly Cl −) (Dhiman et al., 2009 Hampton et al., 1998 Krawisz et al., 1984 Lazarevic-Pasti et al., 2015). The interactions of the top scoring ligands with the ARG C:239 and the Porphyrin rings suggest that the designed drugs can act as inhibitors of MPO in competing with H 2O 2 binding site. The imidazole ring in the drugs contributes to its binding energy through its interaction with the amino acid residue PHE (Phenylalanine) A:99, an important residue of the hydrophobic pocket in the target protein. These scores are comparatively better than the selected reference drugs primaquine (−6.3856 kcal/mol) and salicylhydroxamic acid (−4.5722 kcal/mol). The docking analysis identified ligands 154, 158 and 136 as the top three scoring ligand with a binding score of −7.1329 kcal/mol, −7.0021 kcal/mol and −6.9100 kcal/mol respectively.
The designed drugs were docked with Human Myeloperoxidase (pdb ID: 1DNU ), an active enzyme involved in the cause of inflammation and oxidative stress. The drugs were screened for drug-likeness using SWISS-ADME server and molecular docking analysis were carried out with MOE 09. 164 imidazole-based drugs were designed and their structures were optimized with DFT method.