Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis.

摘要: The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health highlight the need discover develop new, effective inexpensive antituberculosis agents. High-throughput screening assays against well-validated targets structure based design have been employed new lead compounds. However, majority fail demonstrate any antimycobacterial activity when tested Mycobacterium in whole-cell assays. This is mainly due some intrinsic properties bacilli, such as extremely low permeability its cell wall, slow growth, resistance, tolerance persistence. In this sense, understanding pathways involved M. tolerance, persistence pathogenesis, may reveal approaches for development. Moreover, compounds presenting novel mode action utmost importance resistance not only currently used agents, but also those pipeline. Cheminformatics studies shown that drugs endowed with anti-tuberculosis peculiarity being more lipophilic than many other antibacterials, likely because leads improved penetration through waxy mycobacterial wall. interaction moiety membrane alters stability functional integrity disruption proton motive force, resulting death. When ligand-based medicinal chemistry campaign ongoing, it always difficult predict whether chemical modification or group would be suitable improving activity. Nevertheless, “instruction manual” chemists, certain groups physicochemical characteristics (i.e. high lipophilicity) are considered red flags look out order safeguard drug-likeness avoid attritions discovery process. review, we describe how challenge established rules Lipinski’s rule five, must thought beyond dogmatic schemes.