Page - (000064) - in Biomedical Chemistry: Current Trends and Developments

A second widely used strategy is to modulate the reactivity of the electrophilic site in the inhibitor and to optimize the molecular recognition towards the target enzyme. This approach was successfully used to develop selective Michael acceptors inhibitors towards cysteine proteases expressed by several viruses and parasites that are crucial for the development and infectiveness of these infectious agents. Molecular hybridization, where two different pharmacophores are joined through a linker (Meunier, 2008), has also emerged as a useful tool in medicinal chemistry to modulate the reactivity and improve selectivity of toxic compounds, including covalent irreversible inhibitors. These approaches will be dealt in more detail in the following sections. Figure 1.2.2: Mechanism-based covalent inhibitors. For detailed description on their mechanism of action see Silverman, 1992. Fragment-based methods have been developed to rapidly discover selective irreversible covalent inhibitors of cysteine proteases with tempered reactivity. Typically, an initial assessment of the intrinsic reactivity of a panel of low-molecular weight Michael acceptors is performed using papain as a model cysteine-dependent enzyme (Santos, 2007), allowing the selection of the most effective warhead (Kathman, 2014). In this way, a fragment with the most specific binding affinity, rather than the most reactive fragment, might be identified for future optimization. More recently, the concept of reversible covalent inhibitors has emerged as a powerful approach to avoid toxicity issues often associated to the formation of irreversible covalent adducts with off-targets. Although frequently designed to inactivate conserved, catalytically essential cysteines, covalent inhibitors can also achieve maximal selectivity among related targets by exploiting the intrinsic nucleophilicity of poorly conserved, solvent-exposed non-catalytic cysteines (Singh, 2011). Elegant work developed by Taunton and collaborators paved the way to establish the chemical basis for