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 IC₅₀ 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

Inhibitors of the NAD⁺‑Dependent Protein Desuccinylase and Demalonylase Sirt5

NAD⁺-dependent histone deacetylases (sirtuins) play important roles in epigenetic regulation but also through nonhistone substrates for other key cellular events and have been linked to the pathogenesis of cancer, neurodegeneration, and metabolic diseases. The subtype Sirt5 has been shown recently to act as a desuccinylating and demalonylating enzyme. We have established an assay for biochemical testing of Sirt5 using a small labeled succinylated lysine derivative. We present a comparative study on the profiling of several established sirtuin inhibitors on Sirt1–3 as well as Sirt5 and also present initial results on a screening for new compounds that block Sirt5. Thiobarbiturates were identified as new Sirt5 inhibitors in the low micromolar range, which are selective over Sirt3 that can be found in the same cell compartment as Sirt5

Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.

<p>Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.</p

2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.

<p>2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.</p

2D structures of selected promising compounds derived from the African flora and included in AfroDb.

<p>2D structures of selected promising compounds derived from the African flora and included in AfroDb.</p

Pairwise comparison of mutual relationships between molecular descriptors.

<p>(A) The distribution of the calculated log <i>P</i> versus MW, (B) HBA against MW, (C) HBD against MW and (D) NRB versus MW. LCR represents the Lipinski compliant regions.</p

Comparison of property distribution for the two datasets by percentage distributions.

<p>(A) MW, (B) log <i>P</i>, (C) HBA and (D) HBD. DNP in red and AfroDb in blue. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. −2 is equivalent to −2 to −1.</p

Sources and biological activities of metabolites with calculated log <i>P</i>>14 found in AfroDb.

<p>Sources and biological activities of metabolites with calculated log <i>P</i>>14 found in AfroDb.</p

Graph distribution of features that determine “drug-likeness”.

<p>(A, B) Histogram of Lipinski violations as a percentage of the AfroDb data set and molar weight distribution, respectively. (C, D, E, F) Distribution curves of the log <i>P</i>, HBA, HBD and NRB, respectively for the 1,008 compounds currently in AfroDb. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0 to 100.</p

MCSS panel in AfroDb, featuring the most common cyclic structures included in the database.

<p>MCSS panel in AfroDb, featuring the most common cyclic structures included in the database.</p