Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening
Di Zhu, Sandra Johannsen, Tiziana Masini, Céline Simonin, Jörg Haupenthal, Boris Illarionov, Anastasia Andreas, Mahendra Awale, Robin M. Gierse, Tridia van der Laan, Ramon van der Vlag, Rita Nasti, Mael Poizat, Eric Buhler, Norbert Reiling, Rolf Müller, Markus Fischer, Jean‐Louis Reymond, Anna K. H. Hirsch
Abstract
. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action.
Topics & Concepts
Virtual screeningDrug discoveryLigand (biochemistry)DrugComputational biologyChemistryEnzymePharmacologyCombinatorial chemistryBiologyBiochemistryReceptorComputational Drug Discovery MethodsBiochemical and Molecular ResearchATP Synthase and ATPases Research