Computer-based de novo design of drug-like molecules

Abstract

Molecular de novo design, which involves incremental construction of a ligand model within a model of the receptor or enzyme active site, produces novel molecular structures with desired pharmacological properties from scratch. De novo molecule-design software is confronted with a virtually infinite search space. As such a large space prohibits exhaustive searching, navigation in the de novo design process relies on the principle of local optimization. Basically, three questions have to be addressed by a de novo design program: how to assemble the candidate compounds; how to evaluate their potential quality; and how to sample the search space effectively. This review gives an overview of computer-based molecular de novo design methods on a conceptual level, considering these three questions, and focusing on the design of small, drug-like molecules. Successful examples of de novo design in the hit- and lead-finding stages of the drug discovery process are used to show that de novo design provides a method for lead identification. De novo design can therefore be regarded as a complement to other virtual techniques, such as database searching, and non-virtual techniques such as high-throughput screening. We also accentuate strengths and weaknesses of current de novo design approaches.