23 research outputs found
Virtual Screening of PRK1 Inhibitors: Ensemble Docking, Rescoring Using Binding Free Energy Calculation and QSAR Model Development
Protein kinase C Related Kinase 1
(PRK1) has been shown to be involved
in the regulation of androgen receptor signaling and has been identified
as a novel potential drug target for prostate cancer therapy. Since
there is no PRK1 crystal structure available to date, multiple PRK1
homology models were generated in order to address the protein flexibility.
An in-house library of compounds tested on PRK1 was docked into the
ATP binding site of the generated models. In most cases a correct
pose of the inhibitors could be identified by ensemble docking, while
there is still a challenge of finding a reasonable scoring function
that is able to rank compounds according to their biological activity.
We estimated the binding free energy for our data set of structurally
diverse PRK1 inhibitors using the MM-PB(GB)SA and QM/MM-GBSA methods.
The obtained results demonstrate that a correlation between calculated
binding free energies and experimental IC<sub>50</sub> values was
found to be usually higher than using docking scores. Furthermore,
the developed approach was tested on a set of diverse PRK1 inhibitors
taken from literature, which resulted in a significant correlation.
The developed method is computationally inexpensive and can be applied
as a postdocking filter in virtual screening as well as for optimization
of PRK1 inhibitors in order to prioritize compounds for further biological
characterization
Nonpeptidic Propargylamines as Inhibitors of Lysine Specific Demethylase 1 (LSD1) with Cellular Activity
Lysine
demethylases play an important role in epigenetic regulation and thus
in the development of diseases like cancer or neurodegenerative disorders.
As the lysine specific demethylase 1 (LSD1/KDM1) has been strongly
connected to androgen and estrogen dependent gene expression, it serves
as a promising target for the therapy of hormone dependent cancer.
Here, we report on the discovery of new small molecule inhibitors
of LSD1 containing a propargylamine warhead, starting out from lysine
containing substrate analogues. On the basis of these substrate mimicking
inhibitors, we were able to increase potency by a combination of similarity-based
virtual screening and subsequent synthetic optimization resulting
in more druglike LSD1 inhibitors that led to histone hypermethylation
in breast cancer cells
Retinoic acid inhibits monocyte to macrophage survival and differentiation
Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing MO for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells. Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF. Northern analysis showed that the M-CSF mRNA expression was only slightly reduced by RA treatment, suggesting regulation on the posttranscriptional level. In contrast to MO, M-CSF secretion by MO-derived macrophages (MAC) was not altered by RA, suggesting a differentiation-dependent switch in the responsiveness of MO/MAC to RA. Because M-CSF is not only a survival-promoting but also a differentiation-promoting factor for myeloid cells, we analyzed the effect of RA on MO to MAC maturation. RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and modulated the lipopolysaccharide-stimulated cytokine secretion of MO/MAC. The addition of exogenous M-CSF to RA-containing MO cultures fails to overcome the RA-induced inhibition of MO differentiation. However, the survival rate was improved by exogenous M-CSF. We conclude that RA acts via two different mechanisms on monocyte survival and differentiation: posttranscriptionally by controlling M-CSF secretion, which decreases MO survival, and transcriptionally regulating the expression of differentiation-associated genes. The regulation of M-CSF production may contribute to the antileukemic effect of RA in vivo by reducing autocrine M-CSF production by leukemic cells