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3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with K's < 10 μM (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low μM inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.

Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170 -0.360 µM, with indirubin-3'-acetoxime (1c) the most potent. 7-bromoindirubin-3'-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting σ-hole effects is highlighted. A new statistical metric, the 'sum of the modified logarithm of ranks' (SMLR), has been defined which measures performance of a model for both the "early recognition" (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6'(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work.

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N-(β-d-Glucopyranosyl)-1,2,4-triazolecarboxamides discovered as low μM inhibitors of glycogen phosphorylase b.

The human monkeypox virus (MPV), a zoonotic illness that was hitherto solely prevalent in Central and West Africa, has lately been discovered to infect people all over the world and has become a major threat to global health. Humans unintentionally contract this zoonotic orthopoxvirus, which resembles smallpox, when they come into contact with infected animals. Studies show that the illness can also be transferred through frequent proximity, respiratory droplets, and household linens such as towels and bedding. However, MPV infection does not presently have a specified therapy. Smallpox vaccinations provide cross-protection against MPV because of antigenic similarities. Despite scant knowledge of the genesis, epidemiology, and ecology of the illness, the incidence and geographic distribution of monkeypox outbreaks have grown recently. Polymerase chain reaction technique on lesion specimens can be used to detect MPV. Vaccines like ACAM2000, vaccinia immune globulin intravenous (VIG-IV), and JYNNEOS (brand name: Imvamune or Imvanex) as well as FDA-approved antiviral medications such as brincidofovir (brand name: Tembexa), tecovirimat (brand name: TPOXX or ST-246), and cidofovir (brand name: Vistide) are used as therapeutic medications against MPV. In this overview, we provide an outline of the MPV’s morphology, evolution, mechanism, transmission, diagnosis, preventative measures, and therapeutic approaches. This study offers the fundamental information required to prevent and manage any further spread of this emerging virus.

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