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C─H⋯O hydrogen bonds constitute a unique class of cohesive interactions. Their properties are similar to those of canonical H-bonds, although their energy is significantly lower, typically in the 0.5-2.5 kcal/mol range. Polarised C─H groups, such as those adjacent to electronegative groups, or within aromatic moieties, are particularly strong donors. C─H⋯O bonds are ubiquitous in nucleic acids and in proteins, notably stabilizing the β-sheet secondary structure. They have also been observed in numerous protein-ligand interactions. Here, we analysed crystal structures, deposited in the Protein Data Bank, of complexes of FDA-approved protein kinase inhibitors with cognate kinases, to assess the possible role of C─H inhibitor ⋯O protein hydrogen bonds. The conserved hinge motif of protein kinases with two solvent-exposed carbonyl groups and one exposed backbone amide, is well known to be involved in canonical H-bonding with inhibitors. We now find that in virtually all complexes where the inhibitor interacts with the hinge backbone, at least one of the hinge carbonyl groups accepts an H-bond from a C─H inhibitor group, which is either aromatic or adjacent to an electronegative group. These observations are important for design of hinge-binding scaffolds of novel kinase inhibitors for therapeutic use., (© 2020 International Union of Biochemistry and Molecular Biology.)

Extracellular signal-regulated kinase 3 (ERK3 also designated MAPK6 — mitogen-activated protein kinase 6) is a ubiquitously expressed kinase participating in the regulation of a broad spectrum of physiological and pathological processes. Targeted inhibition of the kinase may allow the development of novel treatment strategies for a variety of types of cancer and somatic pathologies, as well as preserving metabolic health, combat obesity and diabetes. We chose and synthesized three triazolo [4,5- d ]pyrimidin-5-amines proposed previously as putative ERK3 inhibitors to assess their selectivity and biological effects in terms of metabolic state impact in living cells. As it was previously shown that ERK3 is a major regulator of lipolysis in adipocytes, we focused on this process. Our new results indicate that in addition to the previously identified lipolytic enzyme ATGL, ERK3 also regulates hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). Moreover, this kinase also promotes the abundance of fatty acid synthase (FASN) as well as protein kinase cAMP-activated catalytic subunit alpha (PKACα). To investigate various effects of putative ERK3 inhibitors on lipolysis, we utilized different adipocyte models. We demonstrated that molecules exhibit lipolysis-modulating effects; however, the effects of triazolo [4,5- d ]pyrimidin-5-amines based inhibitors on lipolysis are not dependent on ERK3. Subsequently, we revealed a wide range of the compounds' possible targets using a machine learning-based prediction. Therefore, the tested compounds inhibit ERK3 in vitro , but the biological effect of this inhibition is significantly overlapped and modified by some other molecular events related to the non-selective binding to other targets. [Display omitted] • ERK3 promotes the abundance of HSL, MGL, FASN, as well as PKACα in adipocytes. • Triazolo [4,5- d ]pyrimidin-5-amines based ERK3 inhibitors exhibit lipolysis-modulating effects. • Effects of triazolo [4,5- d ]pyrimidin-5-amines based ERK3 inhibitors on adipocyte function are not dependent on ERK3. [ABSTRACT FROM AUTHOR]