Flavonoids as CDK1 Inhibitors: Insights in Their Binding Orientations and Structure-Activity Relationship - Fig 5

<p><b>CoMSIA contour maps for CDK1 inhibitors deriving from the best models for the TA (A), DA (B) and DAI (C) alignments.</b> Compound <b>20</b> is shown inside the fields in (A) and (B), and compound <b>4</b> is shown inside the fields in (C). In (B) and (C), the amino acid residues located close to the binding pocket of CDK1 are represented for comparing their position with the position of isopleths derived from the model. Hydrophobic field: yellow isopleths indicate regions where hydrophobic groups favor the activity, and gray isopleths indicate regions where hydrophilic groups favor the activity. HB donor field: cyan isopleths indicate regions where HB donors favor the activity, and purple isopleths indicate regions where HB donors disfavor the activity. Steric field (in C): green isopleths indicates region where bulky groups favor the activity.</p

Template alignment (TA) for all compounds used for CoMFA and CoMSIA.

<p>Template alignment (TA) for all compounds used for CoMFA and CoMSIA.</p

CoMSIA and CoMFA results using the best field combinations^a.

<p>CoMSIA and CoMFA results using the best field combinations<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161111#t003fn001" target="_blank">^a</a>.</p

Binding modes of the compounds under study into CDK1 binding site.

<p>(A) flavones, compounds <b>1</b>–<b>19</b> (B) chalcones with orientation I, compounds <b>31</b>–<b>37</b>, (C) chalcones with orientation II, compounds <b>20</b>–<b>30</b>.</p

Structures of chalcones as CDK1 inhibitors.

<p>Experimental and predicted activities (log(1/IC₅₀)) using models CoMSIA models.</p

Structures of flavones (1–19) and chalcones (20–37).

<p>Structures of flavones (1–19) and chalcones (20–37).</p

Structures of flavones as CDK1 inhibitors.

<p>Experimental and predicted activities (log(1/IC₅₀)) using models CoMSIA models.</p

Computational Analyses of the AtTPC1 (Arabidopsis Two-Pore Channel 1) Permeation Pathway

Two Pore Channels (TPCs) are cation-selective voltage- and ligand-gated ion channels in membranes of intracellular organelles of eukaryotic cells. In plants, the TPC1 subtype forms the slowly activating vacuolar (SV) channel, the most dominant ion channel in the vacuolar membrane. Controversial reports about the permeability properties of plant SV channels fueled speculations about the physiological roles of this channel type. TPC1 is thought to have high Ca2+ permeability, a conclusion derived from relative permeability analyses using the Goldman–Hodgkin–Katz (GHK) equation. Here, we investigated in computational analyses the properties of the permeation pathway of TPC1 from Arabidopsis thaliana. Using the crystal structure of AtTPC1, protein modeling, molecular dynamics (MD) simulations, and free energy calculations, we identified a free energy minimum for Ca2+, but not for K+, at the luminal side next to the selectivity filter. Residues D269 and E637 coordinate in particular Ca2+ as demonstrated in in silico mutagenesis experiments. Such a Ca2+-specific coordination site in the pore explains contradicting data for the relative Ca2+/K+ permeability and strongly suggests that the Ca2+ permeability of SV channels is largely overestimated from relative permeability analyses. This conclusion was further supported by in silico electrophysiological studies showing a remarkable permeation of K+ but not Ca2+ through the open channel

Insights into the Structural Requirements of 2(S)-Amino-6-Boronohexanoic Acid Derivatives as Arginase I Inhibitors: 3D-QSAR, Docking, and Interaction Fingerprint Studies

Human arginase I (hARGI) is an important enzyme involved in the urea cycle; its overexpression has been associated to cardiovascular and cerebrovascular diseases. In the last years, several congeneric sets of hARGI inhibitors have been reported with possible beneficial roles for the cardiovascular system. At the same time, crystallographic data have been reported including hARGI&ndash;inhibitor complexes, which can be considered for the design of novel inhibitors. In this work, the structure&ndash;activity relationship (SAR) of C&alpha; substituted 2(S)-amino-6-boronohexanoic acid (ABH) derivatives as hARGI inhibitors was studied by using a three-dimensional quantitative structure&ndash;activity relationships (3D-QSAR) method. The predictivity of the obtained 3D-QSAR model was demonstrated by using internal and external validation experiments. The best model revealed that the differential hARGI inhibitory activities of the ABH derivatives can be described by using steric and electrostatic fields; the local effects of these fields in the activity are presented. In addition, binding modes of the above-mentioned compounds inside the hARGI binding site were obtained by using molecular docking. It was found that ABH derivatives adopted the same orientation reported for ABH within the hARGI active site, with the substituents at C&alpha; exposed to the solvent with interactions with residues at the entrance of the binding site. The hARGI residues involved in chemical interactions with inhibitors were identified by using an interaction fingerprints (IFPs) analysis