Abstract
Publisher Summary This chapter provides an overview of the application of computational approaches to the design of potent new antibacterial agents for two well-validated infection targets: DNA gyrase and peptide deformylase. The chapter also describes the way structural knowledge combined with various computational tools profoundly influences and accelerates drug discovery by either de novo design of leads or the improvement of existing leads. The analysis of crystal structures and structure-based virtual screening has allowed identification of novel hits and leads in the early stages of drug-discovery projects. The iterative use of structural information and various computational methods has resulted not only in designing more potent enzyme inhibitors but also in optimizing physicochemical properties and antibacterial activity. Despite the successes, there are still many challenges ahead in optimizing computational methods, such as improving scoring functions, accounting for protein flexibility, and proper calculation of solvation. In the future, with the use of X-ray crystal structures of the transporters, inhibitors can be designed that do not bind to transporters and overcoming these challenges should allow structure-based design an even greater impact on drug discovery.
Published Version
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