How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling

Abstract

Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity. Imidazole-based analogues show effective and selective inhibitory potency of HO-1. In this work, five single-crystal structures of four imidazole-based compounds are presented, with an in-depth structural analysis. In order to study the influence of the conformation of the ligands on binding to protein, conformational data from crystallography are compared with quantum mechanics analysis and molecular docking studies. Molecular docking of imidazole-based analogues in the active site of HO-1 is in good agreement with the experimental structures. Inhibitors interact with the heme cofactor and a hydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1 binding site. An alternate binding mode can be hypothesized for some inhibitors in the series.

An Insight into the Biological Properties of Imidazole‐Based Schiff Bases: A Review

“…Correlated crystallography with quantum mechanical and molecular docking data's hence confirmed the effective binding with protein. Inhibitors engaged with the heme cofactor and hydrophobic pockets in the HO‐1 binding site and were once in contrast with a reference inhibitor 1‐methyl‐tryptophan [138] …”

“…[137] Carletta and co-workers (2015) developed four imidazolebased compounds (76)(77)(78)(79) for the inhibition of Heme oxygenase-1 (HO-1) which was associated with antitumor activity ChemistrySelect site and were once in contrast with a reference inhibitor 1methyl-tryptophan. [138] The antioxidant, analgesic and anti-inflammatory activity of benzene fused imidazole Schiff bases had been evaluated by Eswayah et al (2020). Antiinflammatory drugs are individuals from a drug class that diminishes pain, reduces fever, prevent blood clumps, and in higher dosages, diminishes inflammation for a short moment while analgesics can be utilized for both short and long term pain relief.…”

Computational Designing and Prediction of ADMET Properties of Four Novel Imidazole‐based Drug Candidates Inhibiting Heme Oxygenase‐1 Causing Cancers

“…[21] Its derivatives are non-competitive with heme and bind together at the HO-1 binding site. [22,23] Moreover, the derivatives are more selective to HO-1 than HO-2, [24] less active to CYP450, sGC, and NOS, [25] and soluble in water. [26] QC-308, a derivative of azalanstat, showed high potency against HO-1.…”

“…Consequently, azalanstat, an imidazole‐based compound and a non‐porphyrin inhibitor, was recently developed [21] . Its derivatives are non‐competitive with heme and bind together at the HO‐1 binding site [22,23] . Moreover, the derivatives are more selective to HO‐1 than HO‐2, [24] less active to CYP450, sGC, and NOS, [25] and soluble in water [26] .…”