Binding cavities and druggability of intrinsically disordered proteins

Abstract

To assess the potential of intrinsically disordered proteins (IDPs) as drug design targets, we have analyzed the ligand-binding cavities of two datasets of IDPs (containing 37 and 16 entries, respectively) and compared their properties with those of conventional ordered (folded) proteins. IDPs were predicted to possess more binding cavity than ordered proteins at similar length, supporting the proposed advantage of IDPs economizing genome and protein resources. The cavity number has a wide distribution within each conformation ensemble for IDPs. The geometries of the cavities of IDPs differ from the cavities of ordered proteins, for example, the cavities of IDPs have larger surface areas and volumes, and are more likely to be composed of a single segment. The druggability of the cavities was examined, and the average druggable probability is estimated to be 9% for IDPs, which is almost twice that for ordered proteins (5%). Some IDPs with druggable cavities that are associated with diseases are listed. The optimism versus obstacles for drug design for IDPs is also briefly discussed.

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…A relevant strategy is "to inhibit interactions with ordered or disordered protein partners" [52]. In fact, there are only a limited number of IDP-related systems studied in drug design; the small molecule inhibitors were mostly identified by experimental screening without considering the mechanism or the toxic side effects of the inhibition [54,55]. Computational unfoldomics is a recently proposed, emerging concept, which identifies metastable structures by simulations coupled with virtual screen of potential inhibitors [53].…”

Intrinsically Disordered Proteins as Drug Targets

“…This fact is a great contradiction as there are bioinformatics studies showing that Post Translational Modifications (PTMs) prefer disordered regions or that 79% of cancer associated proteins and 57% of the identified cardiovascular disease-associated proteins contain disordered regions of more than 30 residues. 43,44 Compared with drug design pipe-lines for ordered proteins, for IDPs these processes remain in their infancy. 44,45 Actually, the drugs related with IDPs consist on few molecules and some small peptides.…”

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“…This fact is a great contradiction as there are bioinformatics studies showing that Post translational modifications (PTMs) prefer disordered regions or that 79% of cancer associated proteins and 57% of the identified cardiovascular disease-associated proteins contain disordered regions of more than 30 residues [43,44]. Compared with drug design pipe-lines for ordered proteins, for IDPs these processes remain in their infancy [44,45]. Actually, the drugs related with IDPs consist on few molecules and some small peptides [10,42,44].…”

“…Compared with drug design pipe-lines for ordered proteins, for IDPs these processes remain in their infancy [44,45]. Actually, the drugs related with IDPs consist on few molecules and some small peptides [10,42,44]. This happens, among other reasons, because how IDPs perform their diverse function is not well understood.…”

“…Zhang and coworkers [44] have studied the ligand-binding cavities of diverse IDPs comparing some of their properties with those of ordered proteins. They concluded that IDPs are predicted to possess more binding cavities than ordered proteins of a similar length, showing different geometries.…”