Fragment-based drug discovery and protein–protein interactions

Abstract

Protein-protein interactions (PPIs) are involved in many biological processes, with an estimated 400,000 PPIs within the human proteome. There is significant interest in exploiting the relatively unexplored potential of these interactions in drug discovery, driven by the need to find new therapeutic targets. Compared with classical drug discovery against targets with well-defined binding sites, developing small-molecule inhibitors against PPIs where the contact surfaces are frequently more extensive and comparatively flat, with most of the binding energy localized in "hot spots", has proven far more challenging. However, despite the difficulties associated with targeting PPIs, important progress has been made in recent years with fragmentbased drug discovery playing a pivotal role in improving their tractability. Computational and empirical approaches can be used to identify hot-spot regions and assess the druggability and ligandability of new targets, whilst fragment screening campaigns can detect low-affinity fragments that either directly or indirectly perturb the PPI. Once fragment hits have been identified and confirmed using biochemical and biophysical approaches, three-dimensional structural data derived from nuclear magnetic resonance or X-ray crystallography can be used to drive medicinal chemistry efforts towards the development of more potent inhibitors. A small-scale comparison presented in this review of "standard" fragments with those targeting PPIs has revealed that the latter tend to be larger, be more lipophilic, and contain more polar (acid/base) functionality, whereas three-dimensional descriptor data indicate that there is little difference in their three-dimensional character. These physiochemical properties can potentially be exploited in the rational design of PPI-specific fragment libraries and correlate well with optimized PPI inhibitors, which tend to have properties outside currently accepted guidelines for drug-likeness. Several examples of small-molecule PPI inhibitors derived from fragment-based drug discovery now exist and are described in this review, including navitoclax, a novel Bcl-2 family inhibitor which has entered Phase II clinical trials in patients with small-cell lung cancer and chronic lymphocytic leukemia.

Systematic Targeting of Protein–Protein Interactions

“…Drug-like libraries, developed for traditional drug targets, often lack the characteristics needed to engage a protein’s surface[62, 63]. Thus, screening of drug-like compound libraries against PPI surfaces often leads to nonspecific and low affinity hits.…”

“…Thus, screening of drug-like compound libraries against PPI surfaces often leads to nonspecific and low affinity hits. To address these limitations, fragment-based screening techniques have been developed[63, 64]. These techniques work well since modulators of PPIs may be viewed as assemblies of multiple drug-like molecules or fragments stitched together.…”

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

“…From a geometrical point of view, most PPI interfaces have planar shapes [28–30], except for intertwined interface structures [31], and they do not have a groove where a small molecule binds to. In contrast, traditional binding pockets have a concave protein surface [32]. …”

“…MW is heavier), more hydrophobic, and more likely to form hydrogen bonds with proteins than traditional drugs. Due to their highly hydrophobic nature, designing SMPPIIs faces a challenge of bioavailability, which is defined as the proportion of a drug that reaches at the site of action [45]. The authors also mapped the SMPPIIs on the chemico-biological space.…”

Targeting protein–protein interactions in complexes organized by A kinase anchoring proteins

“…Peptides do not have these limitations, but have issues with stability and permeability. In order for small molecule targeting of PPIs to be successful, a topology of the interacting proteins with small pockets or the identification of key residues that contribute to the binding energy, so called “hot spots” are necessary requirements (reviewed in Turnbull et al, 2014 ). Furthermore, increasing the size and molecular weight of the small molecule or assembling new compounds by a fragment-based approach may overcome some of these problems.…”