Strong Descriptors Research Articles

Computational prediction and molecular mechanism of γ-secretase modulators

Selective control over Aβ production via γ-secretase modulators (GSM) is a promising strategy for treating Alzheimer's disease, yet the specific binding sites and mechanism of action of GSMs remain unknown. Using the recent cryo-electron microscopy structures of substrate-bound γ-secretase we used two distinct methods to identify four potential binding sites for pyridopyrazine-1,6-dione GSMs. We demonstrate binding to site 4 formed between PS1-TM2, PS1-TM5 and the APP-C83-TM, with experimental activity data correlating significantly (95% confidence) with our computed binding-affinities for this site. Charged protonated GSMs may display higher affinities because of π-cation interaction with the polar residue Tyr115 of PS1-NTF. Surprisingly, the pIC50 of these compounds is largely described (R2 > 0.4 for all of these) by the molecular size, hydrophobicity, and polarizability. We thus believe that we have identified the primary modulator binding site in γ-secretase for these compounds, as well as strong descriptors of GSM potency. Our results are consistent with the FIST model of γ-secretase action and suggest that GSMs work in two ways: The binding affinity itself contributes stability to the ternary enzyme-modulator-substrate complex (tight grabbing), thus preventing early release of the substrate and increasing trimming to shorter, innocent Aβ peptides. At the same time, drug size, hydrophobicity, and polarizability stabilize the more compact semi-open state over the open PS1 state, to make cleavage more precise and complete.

On correlation of hyperbolic volumes of fullerenes with their properties

AbstractWe observe that fullerene graphs are one-skeletons of polyhedra, which can be realized with all dihedral angles equal to π /2 in a hyperbolic 3-dimensional space. One of the most important invariants of such a polyhedron is its volume. We are referring this volume as a hyperbolic volume of a fullerene. It is known that some topological indices of graphs of chemical compounds serve as strong descriptors and correlate with chemical properties. We demonstrate that hyperbolic volume of fullerenes correlates with few important topological indices and so, hyperbolic volume can serve as a chemical descriptor too. The correlation between hyperbolic volume of fullerene and its Wiener index suggested few conjectures on volumes of hyperbolic polyhedra. These conjectures are confirmed for the initial list of fullerenes.

195 Pt NMR parameters as strong descriptors in one-parameter QSAR models for platinum-based antitumor compounds.

Highly predictive one-parameter quantitative structure-activity relationship models have been developed for platinum-based anticancer drugs using the 195 Pt NMR parameters as strong descriptors. The developed quantitative structure-activity relationship models were applied in diverse homogeneous sets of antiproliferative Pt(II) and Pt(IV) compounds. These observations form the basis for making predictions of cytotoxicity for a broad range of platinum-based antitumor compounds just from inspection of calculated or experimentally determined 195 Pt NMR parameters. Copyright © 2016 John Wiley & Sons, Ltd.

Discriminative Analyses of Various Upper Body Tests in Professional Rugby-League Players

To examine the upper body strength, speed, power, and strength-endurance of rugby-league players of different ranks. These data could provide information pertinent to the importance of these factors for different grades of rugby league and for positional groups in those different grades. Sixty rugby-league players, 20 participants each in the elite, national first-division league (NRL), state-based second-division league (SRL), and intracity third-division league (CRL), served as subjects. Maximal upper body strength, power, speed, and muscle endurance were assessed using the bench-press exercise. The NRL players were significantly stronger (141.4 +/- 15.4 kg) than SRL (126.6 +/- 13.1 kg, ES = 1.033) and CRL (108.1 kg +/- 11.6, ES = 2.458) and more powerful (NRL = 680 +/- 99 W) than SRL (591 +/- 72 W, ES = 1.037) and CRL players (521 +/- 71 W, ES = 1.867). The differences in speed (NRL = 345 +/- 31 W, SRL = 319 +/- 29 W, CRL = 303 +/- 29 W; ES = 0.884 and 1.409, respectively) and strength-endurance (NRL = 36 +/- 7 reps, SRL = 32 reps +/- 7, CRL = 24 +/- 5 reps; ES = 0.521 and 1.984, respectively) were not as pronounced. Of the tests undertaken, maximal strength best describes players who attain NRL ranking. Maximum power and strength-endurance were also strong descriptors of attainment of NRL level. Upper body speed appears less likely to strongly discriminate between players who attain NRL level and those who do not. These results tended to hold true across the different team positional groupings.