Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function

Binding free energy calculations of Adenosine Deaminase inhibitors

The interactions between four inhibitors and adenosine deaminase (ADA) were examined by calculating their binding free energies after molecular dynamics simulations. A bonded model was used to represent the electrostatic potentials of the zinc coordination site. The charge distribution of the model was derived by using a two-stage electrostatic potential fitting calculations. The calculated binding free energies are in good agreement with the experimental data and the ranking of binding affinities is well reproduced. Notably, our findings suggest that non-polar contributions play an important role for ADA-inhibitor interactions

Enhancer and Competitive Allosteric Modulation Model for G-protein Coupled Receptors

A new mathematical model, referred to as Enhancer and Competitive Allosteric Modulator (ECAM) model, developed with the aim of quantitatively describing the interaction of an allosteric modulator with both enhancer and competitive properties towards G-protein-coupled receptors is described here. Model simulations for equilibrium (displacement-like and saturation-like), and kinetic (association and dissociation) binding experiments were performed. The results showed the ability of the model to interpret a number of possible ligand-receptor binding behaviors. In particular, the binding properties of PD81723, an enhancer and competitive allosteric modulator for the adenosine A(1) receptor, were experimentally evaluated by radioligand binding assays and interpreted by the ECAM model. The results also offer a theoretical background enabling the design and optimization of compounds endowed with allosteric enhancer, competitive, agonist, antagonist, and inverse agonist properties

Application of Cascade-Correlation Networks for Structures to Chemistry

none4We present the application of Cascade Correlation for structures to QSPR (quantitative structure-property relationships) and QSAR (quantitative structure-activity relationships) analysis. Cascade Correlation for structures is a neural network model recently proposed for the processing of structured data. This allows the direct treatment of chemical compounds as labeled trees, which constitutes a novel approach to QSPR/QSAR. We report the results obtained for QSPR on Alkanes (predicting the boiling point) and QSAR of a class of Benzodiazepines. Our approach compares favorably versus the traditional QSAR treatment based on equations and it is competitive with 'ad hoc' MLPs for the QSPR problem.noneBIANUCCI A.M; MICHELI A; SPERDUTI A.; STARITA ABIANUCCI A., M; Micheli, A; Sperduti, Alessandro; Starita, A

A DFT Investigation of the Addition Reaction of Monomeric Lithium Enolate Derived from Propiophenone to Propene Oxide: Examination of the Possible Transition Structures

The addition reaction of monomeric lithium enolate (Z)-1, derived from propiophenone, to propene oxide 2, was examined to clarify the exact geometry of the transition state (TS) involved in this type of reaction. The eight possible TSs and the corresponding pathways, four leading to syn γ-hydroxy ketone (γ-HK) 3 and four leading to anti γ-HK 4, were compared, using the B3LYP/6-31+G(d)//B3LYP/6-31+G(d) theory level in vacuo and in the presence of the reaction solvent (toluene/hexane). In every case, the favored pathway involves a TS where the enolate CC and the epoxide C−C are in a gauche relationship and where the Li+ is stabilized by some C−C and C−H σ bonds of epoxide 2

IDENTIFICATION OF "TOXICOPHORIC" FEATURES FOR PREDICTING DRUG-INDUCED QT INTERVAL PROLONGATION

Drugs delaying cardiac repolarization by blockade of hERG K(+) channel generally prolong the QT interval of the electrocardiogram, an effect regarded as a cardiac risk factor with the potential to cause 'torsade des pointes'-type arrhythmias in humans. The present study applied a homology building technique and molecular dynamics simulations to model the pore of hERG K(+) channel. A docking analysis was then performed on selected ligands which were classified as QT-prolonging or non-prolonging after experimental measurements in in vivo anesthetized guinea pig. The results of this structural analysis provided a "toxicophoric" model that was further exploited to inspect a dataset of known QT-prolonging/non-prolonging molecules. The emerging major chemical features to be avoided, in order to obtain cardiac safe therapeutic agents, comprise the simultaneous presence of (i) a protonated nitrogen atom within an observed range of distances from a heteroatom; (ii) aromatic groups capable of interacting within an area defined by Gly657 residues of the pore or within an area located at the top of the longitudinal axis of the pore. Moreover, additional hydrophobic moieties interacting with one of the equatorial cavities located in the area near-by Tyr652 residues and/or with a hydrophobic ring defined by Phe656 residues should be avoided