SummaryThe ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.

Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure-activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition.

A SARS-CoV-2 main protease (MPRO) inhibitor was discovered employing molecular docking and a fragment-based pharmacophore model as virtual screening strategies.

The medicinal chemist plays the most important role in drug design, discovery and development. The primary goal is to discover leads and optimize them to develop clinically useful drug candidates. This process requires the medicinal chemist to deal with large sets of data containing chemical descriptors, pharmacological data, pharmacokinetics parameters, and in silico predictions. The modern medicinal chemist has a large number of tools and technologies to aid him in creating strategies and supporting decision-making. Alongside with these tools, human cognition, experience and creativity are fundamental to drug research and are important for the chemical intuition of medicinal chemists. Therefore, fine-tuning of data processing and in-house experience are essential to reach clinical trials. In this article, we will provide an expert opinion on how chemical intuition contributes to the discovery of drugs, discuss where it is involved in the modern drug discovery process, and demonstrate how multidisciplinary teams can create the optimal environment for drug design, discovery, and development.