Structure-based Design for Medicinal Chemists

Abstract

Structure-based design is an essential part of medicinal chemistry. The availability of experimental structures for many drug discovery targets and improvements in molecular modeling software makes it practical for medicinal chemists to do their own modeling and design. We will focus on how we've seen structure-based design performed during many medicinal chemistry projects in industry. Structure-based design relies most critically on a solid understanding of physical organic chemistry, especially conformational analysis and intra- and intermolecular interactions, and these aspects are covered in depth together with illustrative case studies. The amazing rapid advances in cryo-EM over the last several years are the most exciting and dramatic advance for structure-based design since the previous edition of this book. Those advances have enabled structure determination of membrane proteins and large protein complexes. The breakthroughs in protein structure prediction made by AlphaFold and RoseTTAFold are also considered. Future directions for application of structure-based drug design are considered including use of machine learning and large-scale virtual screening, and PROTAC and molecular glue design.