ABSTRACT
The 17th EFMC Short Course on Medicinal Chemistry took place April 23-26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein Degradation (full title: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development). The course was oversubscribed, with 35 attendees and 6 instructors mainly from Europe but also from the US and South Africa, and representing both industry and academia. This report summarizes the successful event, key lectures given and topics discussed.
Subject(s)
Chemistry, Pharmaceutical , Drug Design , Europe , Proteolysis , South AfricaABSTRACT
Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.
Subject(s)
HSP70 Heat-Shock Proteins/antagonists & inhibitors , HSP70 Heat-Shock Proteins/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Adenosine Triphosphate/metabolism , Binding Sites/drug effects , Drug Discovery , HSP70 Heat-Shock Proteins/chemistry , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Domains/drug effectsABSTRACT
There have been several diagnostic labels for persistent, excessive sexual behaviors, often referred in the popular media as sex addiction. Two related diagnoses, Internet addictive disorder and hypersexual disorder, were considered for, but not included in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. However, most clinicians, even those trained in sexual disorders or addiction medicine, have little to no training in treating sexual compulsivity and cybersex addiction. The authors present the historical context, proposed diagnostic criteria, evaluation protocols, comorbid disorders, speculations about the neuroscience, and treatment recommendations.
