Between Descriptors and Properties: Understanding the Ligand Efficiency Trends for G Protein-Coupled Receptor and Kinase Structure–Activity Data Sets

The chemical meaning of the ligand efficiency (LE) metrics is explained in this paper using a large G protein-coupled receptor (GPCR) and kinase structure–activity (IC₅₀, <i>K</i>_i) data set. Although there is a controversy in the literature regarding both the mathematical validity and the performance of LE, it is in common use as an early estimator for drug optimization. Apparently, the numerous con arguments are not convincing enough. We show here for the first time that the main misunderstanding of the chemical meaning of LE is its interpretation as a molecular descriptor connected with a single molecule. Instead, LE should be interpreted as a statistical property. We show that the LE, which is designed as a regression of a binding property on the heavy atom count (HAC), is correlated to the reciprocal of the molecular weight because of Avogadro statistics. This indicates that the hyperbolic model of LE is basically a consequence of a nonbinding effect, an increase in the number of ligands that are available to a receptor for smaller molecules, and not a real increase in the binding potency for a single HAC as interpreted in the literature. Accordingly, we need to revisit and carefully reevaluate LE-based molecular comparisons

Piperazinyl fragment improves anticancer activity of Triapine

<div><p>A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds–DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L¹-L¹². The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line’s specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further <i>in vivo</i> examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.</p></div

Piperazinyl fragment improves anticancer activity of Triapine - Fig 3

<p>(a) Absorption spectrophotometric titration vs. pH of the free L² ligand; (b) electronic spectra of the protonated species of L²; (c) concentration distribution curves for the L² species. (I = 0.1 M (KCl) in 80% (w/w) MeOH/H₂O; T = 25.0°C; [L²] = 5x10^-5M; pH 1.6–11.02).</p

EDXRF spectra of Au/SiO₂ (a), Au-Fe (b), Au/Cu (c) and Au/Ni(d) that were collected using an Rh target X-ray tube operated at 30kV and 300 μA.

<p>EDXRF spectra of Au/SiO₂ (a), Au-Fe (b), Au/Cu (c) and Au/Ni(d) that were collected using an Rh target X-ray tube operated at 30kV and 300 μA.</p

Design strategy for novel TSCs (L¹-L¹²).

<p>All designed ligands are based on the Triapine skeleton, which is present in the active analogs Dp44mT, DpC and 1b, 1d that have been described as highly active analogs [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188767#pone.0188767.ref021" target="_blank">21</a>].</p

Protonation constants (log<i>β</i> ^H) of the L¹-L¹² ligands in the MeOH/H₂O mixed solution^a.

<p>Protonation constants (log<i>β</i> ^H) of the L¹-L¹² ligands in the MeOH/H₂O mixed solution<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188767#t001fn001" target="_blank">^a</a>.</p

Ni-Supported Pd Nanoparticles with Ca Promoter: A New Catalyst for Low-Temperature Ammonia Cracking

<div><p>In this paper we report a new nanometallic, self-activating catalyst, namely, Ni-supported Pd nanoparticles (Pd_NPs/Ni) for low temperature ammonia cracking, which was prepared using a novel approach involving the transfer of nanoparticles from the intermediate carrier, i.e. nano-spherical SiO₂, to the target carrier technical grade Ni (t-Ni) or high purity Ni (p-Ni) grains. The method that was developed allows a uniform nanoparticle size distribution (4,4±0.8 nm) to be obtained. Unexpectedly, the t-Ni-supported Pd NPs, which seemed to have a surface Ca impurity, appeared to be more active than the Ca-free (p-Ni) system. A comparison of the novel Pd_NPs/Ni catalyst with these reported in the literature clearly indicates the much better hydrogen productivity of the new system, which seems to be a highly efficient, flexible and durable catalyst for gas-phase heterogeneous ammonia cracking in which the TOF reaches a value of 2615 mmol_H2/g_Pd min (10,570 mol_NH3/mol_Pd(NP) h) at 600°C under a flow of 12 dm³/h (t-Ni).</p></div

Electronic absorption spectra of the Cu(II) and Fe(III)-L²; L⁴; L⁸ system recorded at various metal to ligand ratios.

<p>I = 0.1 M (KCl) in 80% (w/w) MeOH/H₂O; T = 25.0°C; [L] = 5x10^-5M.</p

Anti-proliferative activity (IC₅₀ values) of the novel Triapine analogs compared to Triapine in several tumor cell-types and normal human dermal fibroblast (NHDF) cells.

<p>Individual IC50 values IC50 < 1μM, IC50 1–10 μM, IC50 > 10 μM are coded by red, yellow and grey, respectively.</p

Ammonia conversion on the Pd/Ni (t-Ni catalyst) for different ammonia flow rates of 2 dm³/h (black triangles), 6 dm³/h (shadowed triangles) or 12 dm³/h (white triangles) compared with the control Ni carrier that was preprocessed analogously (but without Pd NPs) at a flow rate of 2 dm³/h (black squares).

<p>Ammonia conversion on the Pd/Ni (t-Ni catalyst) for different ammonia flow rates of 2 dm³/h (black triangles), 6 dm³/h (shadowed triangles) or 12 dm³/h (white triangles) compared with the control Ni carrier that was preprocessed analogously (but without Pd NPs) at a flow rate of 2 dm³/h (black squares).</p