Intrinsically disordered proteins and novel strategies for drug discovery

There is a natural abundance of intrinsically disordered proteins or intrinsically disordered protein regions (IDPs or IDPRs), that is, biologically active proteins/regions without stable structure. Their wide functional repertoire; the ability to participate in multiple interactions; the capability to fold at binding in a template-dependent manner and their common involvement in the pathogenesis of numerous human diseases suggest that these proteins should be seriously considered as novel drug targets.

This article describes the major classes of ordered proteins traditionally used as drug targets and introduces the molecular mechanisms of drugs targeting ordered proteins. Furthermore, it illustrates basic ways of rational drug design for these proteins, and shows why these approaches cannot be directly used for intrinsic disorder-based drug design. Some of the new approaches utilized for finding drugs targeting IDPs/IDPRs are introduced.

There is a continuing progress in the design of small molecules for IDPs/IDPRs and several small molecules are found that specifically inhibit the disorder-based interaction of IDPs with their numerous partners. It is expected that the initial studies will be extended and novel intrinsic disorder-based drug design approaches will be developed. Furthermore, putative new targets will be identified, and a better understanding of the molecular mechanisms underlying modulation of promiscuous IDP binding will be achieved.