In silico fragment-based drug design

Abstract

Importance of the field: In silico fragment-based drug design (FBDD) is a relatively new approach inspired by the success of the biophysical fragment-based drug discovery field. Here, we review the progress made by this approach in the last decade and showcase how it complements and expands the capabilities of biophysical FBDD and structure-based drug design to generate diverse, efficient drug candidates.

Areas covered in this review: Advancements in several areas of research that have enabled the development of in silico FBDD and some applications in drug discovery projects are reviewed.

What the reader will gain: The reader is introduced to various computational methods that are used for in silico FBDD, the fragment library composition for this technique, special applications used to identify binding sites on the surface of proteins and how to assess the druggability of these sites. In addition, the reader will gain insight into the proper application of this approach from examples of successful programs.

Take home message: In silico FBDD captures a much larger chemical space than high-throughput screening and biophysical FBDD increasing the probability of developing more diverse, patentable and efficient molecules that can become oral drugs. The application of in silico FBDD holds great promise for historically challenging targets such as protein–protein interactions. Future advances in force fields, scoring functions and automated methods for determining synthetic accessibility will all aid in delivering more successes with in silico FBDD.

Keywords::

• binding site identification
• docking
• druggability
• fragment-based drug discovery
• in silico fragment-based drug discovery
• structure-based design
• virtual fragment-based drug discovery

Acknowledgements

The author thanks A Klon, C Reynolds, M Kelly and B Liu for reviewing the article.

Notes

This box summarizes key points contained in the article.