Steroid hormones regulate a wide range of physiological processes in the human body. However, exposure to xenobiotics can disrupt the hormonal balance by inhibition of enzymes involved in hormone synthesis or metabolism. Aldo-keto reductase 1D1 (AKR1D1) plays a key role in bile acid and steroid hormone metabolism by catalyzing the reduction of the double bond between C4 and C5 atoms of Δ(4)-steroids. In our previous work, we developed a model to screen for steroid-like xenobiotics that inhibit AKR1D1. In the current study, we used this model to screen for novel non-steroidal inhibitors. By applying an automatized screening approach, based on molecular docking and scoring in combination with post-docking refinement, 45 compounds were detected as potential hits and selected for in vitro evaluation. Among them, zardaverine was identified as the most potent inhibitor, with an IC₅₀ value of 2.32 ± 1.27 μM. Other moderate inhibitors included carbamazepine, larotrectinib, endosulfan II, megastigmatrienone A, and mizolastine. The structural diversity of the identified inhibitors demonstrates that the binding site of AKR1D1 is rather promiscuous and can accommodate a broad range of ligands. These findings underscore the importance of toxicity screening and potential to identify structurally different AKR1D1 inhibitors.

01 Jun 2024·Cell Chemical Biology

Velcrin compounds activate the SLFN12 tRNase to induce tomoptosis

Article

Author: Greulich, Heidi

Velcrins are molecular glues that induce complex formation between PDE3A and SLFN12. The PDE3A-SLFN12 complex activates the SLFN12 RNase, resulting in cleavage of the specific substrate, tRNA-Leu-TAA, global inhibition of translation, and death of cells expressing sufficient levels of both proteins. Here, unanswered questions about the mechanism of action and therapeutic promise of velcrin compounds are discussed.

13 Apr 2023·Journal of Biomolecular Structure and Dynamics

Insights into the potential of withanolides as Phosphodiesterase-4 (PDE4D) inhibitors

Article

Author: Kumar, Vipul ; Rathi, Aditya ; Sundar, Durai

Medicinal herbs have been used as traditional medicines for centuries. The molecular mechanism of action of their bioactive molecules against various diseases or therapeutic targets is still being explored. Here, the active compounds (withanolides) of a well-known Indian medicinal herb, Ashwagandha (Withania somnifera), have been studied for their most potential therapeutic targets and their mechanism of action using ligand-based screening and receptor-based approaches. Ligand-based screening predicted the six top therapeutic targets, namely, Protein kinase C alpha (PRKCA), Protein kinase C delta (PRKCD), Protein kinase C epsilon (PRKCE), Androgenic Receptor (AR), Cycloxygenase-2 (PTGS-2) and Phosphodiesterase-4D (PDE4D). Further, when these predictions were validated using receptor-based studies, i.e. molecular docking, molecular dynamics simulation and free energy calculations, it was found that PDE4D was the most potent target for four withanolides, namely, Withaferin-A, 17-Hydroxywithaferin-A, 27-Hydroxywithanone and Withanolide-R. These compounds had a better binding affinity and similar interactions as that of an already known inhibitor (Zardaverine) of PDE4D. These results warrant further in-vitro and in-vivo investigations to examine their therapeutic potential as an inhibitor of PDE4D.Communicated by Ramaswamy H. Sarma.

100 Deals associated with Zardaverine

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KEGG	Wiki	ATC	Drug Bank
-	Zardaverine	-	DB02918

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	Germany	ALTANA Pharma AG	-
Asthma	Phase 2	-	ALTANA AG	-

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