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Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics. [ABSTRACT FROM AUTHOR]