Biomedical Engineering Reference
In-Depth Information
MACROCYCLES AS TEMPLATES
FOR DIVERSITY GENERATION IN
DRUG DISCOVERY
ERIC MARSAULT
8.1
INTRODUCTION
Macrocycles occupy a distinct segment of the chemical space compared to traditional
small molecules. They have been described as an intermediate class between small
molecules and larger biomolecules, borrowing features of both classes [1]. At one end
of the spectrum, small molecules have been the main objective of drug discovery for
several decades, owing primarily to their favorable PK-ADME (pharmacokinetics,
absorption, distribution, metabolism, and excretion) properties and synthetic acces-
sibility. Small molecules are the target of numerous and versatile synthetic strategies
as well as the object of massive structural and computational support [2]. Numer-
ous molecular descriptors have been refined in the attempt to predict their properties,
starting with Lipinski's rule of 5 [3]. The elucidation of their mode of interaction with
biological targets has been the object of numerous studies, and they have been the
objective of most diversity-oriented synthesis (DOS) approaches within their chem-
ical space (see also Chapters 10, 15-18) [4]. At the other end of the spectrum are
found biological drugs, which have witnessed steady growth for the past two decades.
Proteins occupy the lion's share of this chemical space, particularly antibodies [5].
Biomolecules generally possess large interacting surfaces with their targets, often
featuring distant epitopes, and have proven their high potential for difficult targets
such as protein-protein interactions [6]. Nevertheless, their molecular size gener-
ally prevents them from crossing biological membranes, makes them susceptible to
