Small molecules directly and indirectly affect protein networks

Protein-protein interaction (PPI) networks connect each component of cellular life. Human illness is characterized by dysfunction in PPI network construction or dynamics, and as a result, there is rising interest in the identification of small molecules that either stimulate or inhibit PPIs. Due to their challenging topologies and very huge buried surface areas, PPIs were originally thought to be unhackable.

Despite these difficulties, several of these targets have become more approachable as a result of recent developments in chemical screening techniques, together with advancements in computational and structural biology.

We highlight new advancements that have made powerful chemical modulators possible in this study. We concentrate on the application of allostery, which results in unexpectedly substantial PPI changes, even for the most difficult objectives. We also go through how disrupting one PPI might cause changes to spread over a larger network of relationships. It is becoming evident from our investigation that small molecules eventually reshape biology via a mix of direct and disseminated impacts on PPI networks.

Overview

A core enzyme such a kinase, phosphatase, protease, or nuclease is often the focal point of multi-protein complexes. The "core" enzyme's interactions with adaptor and scaffolding proteins often guide it to certain subcellular sites and/or control its enzymatic activity.

For instance, interactions between the enzyme and a different partner, protein B, may alter the activity, while protein A may trap a certain conformer of the enzyme to promote a particular result. Numerous non-enzymes also regulate the core enzyme's substrate access, affecting its selectivity. For instance, protein A may bind a particular enzyme substrate, so boosting its local availability and speeding up turnover. A mix of strong and weak interactions between the various protein constituents often facilitates the construction of multi-protein complexes. In order to facilitate easy component interchange, weak interactions are utilized.

Multi-protein complexes often operate as "hubs" in a wider protein-protein interaction (PPI) network, extending beyond these direct binding partners. Through a physical network of PPIs, these auxiliary interactions connect the core and its partners to the larger cellular systems. It is becoming more obvious that chemical changes to a single node within the PPI network may have effects that extend much beyond the local area.

The last thoughts, along with some prospective

The "hubs" of cellular PPI networks are multiprotein complexes, which make them interesting therapeutic targets for a number of illnesses. In this study, we've highlighted a number of "success stories" using PPI-targeting small molecules and innovative approaches to the discovery of PPI modulators. Although there is no formula or "road map" for a successful screen, innovative HTS tactics are starting to broaden the arsenal of options.

Instead, each campaign must be specifically developed, taking into consideration the system's many parts' interconnections as well as the affinity of the contacts and the topology of the interaction surfaces. For instance, the greatest likelihood of identifying Small molecules that can disrupt protein networks is via a phenotypic or gray-box screen. These methods, however, need a thorough understanding of the structure and operation of specific PPIs within a larger protein complex, emphasizing the value of fundamental research in order to be able to formulate pertinent questions.