Step‐by‐step design of proteins for small molecule interaction: A review on recent milestones

Protein design is the field of synthetic biology that aims at developing de novo custom‐made proteins and peptides for specific applications. Despite exploring an ambitious goal, recent computational advances in both hardware and software technologies have paved the way to high‐throughput screening and detailed design of novel folds and improved functionalities. Modern advances in the field of protein design for small molecule targeting are described in this review, organized in a step‐by‐step fashion: from the conception of a new or upgraded active binding site, to scaffold design, sequence optimization, and experimental expression of the custom protein. In each step, contemporary examples are described, and state‐of‐the‐art software is briefly explored.