Liliana Pacureanu

Wittig and Wittig-Horner reactions under phase transfer catalysis conditions

Wittig and Wittig-Horner reactions are favorite tools in preparative organic chemistry. These olefination methods enjoy widespread and recognition because of their simplicity, convenience, and effciency. Phase transfer catalysis (PTC) is a very important method in synthetic organic chemistry having many advantages over conventional, homogenous reaction procedures. In this paper, we attempt to summarize the aspects concerning Wittig and Wittig-Horner reactions that take place under phase transfer catalysis conditions.

Retrospective group fusion similarity search based on eROCE evaluation metric.

In this study, a simple evaluation metric, denoted as eROCE was proposed to measure the early enrichment of predictive methods. We demonstrated the superior robustness of eROCE compared to other known metrics throughout several active to inactive ratios ranging from 1:10 to 1:1000. Group fusion similarity search was investigated by varying 16 similarity coefficients, five molecular representations (binary and non-binary) and two group fusion rules using two reference structure set sizes. We used a dataset of 3478 actives and 43,938 inactive molecules and the enrichment was analyzed by means of eROCE. This retrospective study provides optimal similarity search parameters in the case of ALDH1A1 inhibitors.

PLS and shape-based similarity analysis of maleimides – GSK-3 inhibitors

Abstract Context: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer’s disease, cancer, inflammation, obesity, etc. Objective: The aim of the current investigation was to model the inhibitory activity of maleimide derivatives – inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure--Activity Relationship (QSAR) and the effect of the template on shape-similarity – binding affinity relationship. Materials and methods: Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated. Results: Reliable statistics  = 0.938/0.920,  = 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained. Discussion and conclusions: The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility.

Aromatic heterocycles XII. Semiempirical PM3 study of Diels-Alder cycloaddition reaction of substituted phosphabenzenes

We report the results of a semiempirical PM3 study of the 1,4 cycloaddition reaction of substituted λ3-phosphabenzenes with alkynes. The influence of the nature, position and steric hindrance of substituents on the reaction energy is studied. Except for some values, the results are in reasonable agreement with experimental observations and electronic effects of substituents.

QSAR study and molecular docking on indirubin inhibitors of Glycogen Synthase Kinase-3

The current study describes the development of in silico models based on a novel alternative of the MTD-PLS methodology (Partial-Least-Squares variant of Minimal Topologic Difference) developed by our group to predict the inhibition of GSK-3β by indirubin derivatives. The new MTD-PLS methodology involves selection rules for the PLS equation coefficients based on physico-chemical considerations aimed at reducing the bias in the output information. These QSAR models have been derived using calculated fragmental descriptors relevant to binding including polarizability, hydrophobicity, hydrogen bond donor, hydrogen bond acceptor, volume and electronic effects. The MTD-PLS methodology afforded moderate but robust statistical characteristics (R2Y(CUM) = 0.707, Q2(CUM) = 0.664). The MTD-PLS model obtained has been validated in terms of predictive ability by joined internal-external cross-validation applying Golbraikh-Tropsha criteria and Y-randomization test. The information supplied by the MTD-PLS model has been evaluated against Fujita-Ban outcomes that afforded a statistically reliable model (R2=0.923). Furthermore, the results originated from QSAR models were laterally validated with docking insights that suggested the substitution pattern for the design of new indirubins with improved pharmacological potential against GSK-3β. The new restriction rules introduced in this paper are applicable and provide reliable results in accordance with physico-chemical reality.

Challenges in docking 2′-hydroxy and 2′,4′-dihydroxychalcones into the binding site of ALR2

Polyhydroxylated chalcones are able to efficiently inhibit aldose reductase (ALR2; EC 1.1.1.21), an enzyme implicated in the development of diabetic complications. In this study, we performed docking experiments on a series of 38 2′-hydroxy and 2′,4′-dihydroxychalcones with measured inhibitory activities. We demonstrate that docking the chalcones into a single ALR2 active site conformation oversimplifies the attempt to find a probable binding model. Scoring functions exerted relative low agreement concerning a common ALR2 conformation, and suggest that relative to the substituents, chalcones bind to different ALR2 conformations. We found plausible binding modes of 2′,4′-dihydroxychalones for both closed- and open-state conformations of the ALR2 active site, while 5′-chloro, 2′-hydroxychalcones would bind into an ITB (2-(carboxymethyl)-1,3,3-trioxo-benzo[e][1,2]benzothiazole-4-carboxylic acid)-like binding site conformation. The relative poor reliability of docking programs to recognize a ligand binding into a closed- or open-form conformation of the ALR2 binding site was highlighted by a cross-docking experiment of the native ligands. In this context, we employed conditional interference forests to build classification models aiming to predict the conformational state of the ALR2 ligand-binding site in complex with chalcone derivatives. Internally and externally validated models suggest that 2′-hydroxy and 2′,4′-dihydroxichalones leave the specificity pocket closed. Another issue discussed in the current paper concerns the errors related to the average position of the atoms in the crystals, which can heavily influence the docking poses. The diffraction-component precision index (DPI) is able to reflect these errors, but some structures have no calculated values. In a comparative experiment on 55 ALR2 crystal structures, we found the Blow DPI to better approximate the Cruickshank DPI compared to Goto.

XIII. Phosphorus Macrocycles–Theoretical Study

A theoretical study of silacalix[n]phosphinine, n = 3,4 at semiempirical level RHF approximation was performed. Molecular conformation, obtained as local minimum from semiempirical calculation, bond distances and bond angles are in good agreement with X-ray experimental geometry. The values of total energies showed silacalix[4]phosphinine more stable but heats of formation emphasized silacalix[3]phosphinine more stable thermodynamically. Complexation abilities were appreciated by assignment of n andπ∗levels of silacalix[n]phosphinine. Result an improvement ofσ-donating properties and goodπ-acceptor character was kept.

Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors

The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed. A five-point pharmacophore model was built consisting of a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and two rings (RR). An atom-based 3D quantitative structure–activity relationship (QSAR) model showed good correlative and satisfactory predictive abilities (training set

Implementation of PLS discriminant analysis to rank indirubin derivatives against decoys

{R}^{2}= 0.904