Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 3: Design and Selection of Small Molecule Inhibitors

Jianwei Che

Yi Liu

Nathanael S. Gray

Genomics Institute of the Novartis Research Foundation, San Diego, California

Harvard Medical School, Dana Farber Cancer Institute, Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts

The discovery and optimization of small-molecule inhibitors for the treatment of human disease has been the major focus of the pharmaceutical industry for more than a century. In the last decade, they have also attracted increased attention from academia because they provide a powerful means to interrogate biologic systems in an acute fashion. Although pharmaceutical companies have identified many small-molecule inhibitors for drug targets, to find a desirable small-molecule inhibitor for a specific target is still a major challenge for drug discovery and for chemical biology. Here, we present an overview of the computational approaches that can be exploited to discover small-molecule inhibitors for protein targets of interest.

Small molecule inhibitors are of special value to chemical biology and to drug discovery. Thousands of small molecules have been developed as drugs to treat various human diseases. Increasingly, small-molecule inhibitors are used to perturb the function of proteins to elucidate their biologic functions [1, 2]. Complementary to the conventional genetics, small molecules allow rapid, conditional, and tunable inhibition. Furthermore, small molecules can often be ...