The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.
KEYWORDS:Myeloperoxidase, reversible and irreversible inhibitors, dynamic combinatorial chemistry, molecular docking, kinetic study N eutrophils represent the first line of the human innate immune defense system by phagocytosing and killing invading pathogens.1 Optimal antimicrobial action in neutrophils relies on the action of hypochlorous acid (HOCl), the product of the myeloperoxidase (MPO, EC 1.11.2.2)−hydrogen peroxide−chloride system. In certain inflammatory events, MPO and/or HOCl are released from neutrophils causing oxidative damage of host tissue and modification of biomolecules.2−4 Consequently, MPO has become a new target for designing anti-inflammatory drugs.
5−7From a general point of view, the development of pharmacophores typically proceeds according to a conventional pathway, namely, the structural design and synthesis of analogues from a "hit" molecule followed by the evaluation of structure−activity relationships. 6,8 However, this classical method is particularly costly and time-consuming. Another innovative strategy consists in the generation and screening of a dynamic combinatorial library (DCL). 9 In the realm of dynamic combinatorial chemistry (DCC), DCL constitutes a rational alternative in drug discovery, opening thus new horizons for medicinal chemists. Indeed, the in situ reaction of simple building blocks is able to give rise to a wide range of new molecules through reversible covalent bond formation. In the last 10 years, this strategy allowed for the creation and the identification of ligands that specifically recognize targets such as proteins and nucleic acids.
10With this in mind, we decided to apply this approach in order to develop new irreversible inhibitors of MPO. Recently, we evaluated a new family of scaffolds, i.e., hydralazine 11 and isoniazid, endowed with the ability to inhibit MPO irreversibly but with high IC 50 values (0.9 and 5 μM, respectively) ( Figure 1). Keen to improve these substrates, we decided to take advantage of the high reactivity of hydrazine and hydrazide functionalities toward aldehyde partners in order to prepare
