Noise reduction method for molecular interaction energy: application to in silico drug screening and in silico target protein screening

We developed a new method to improve the accuracy of molecular interaction data using a molecular interaction matrix. This method was applied to enhance the database enrichment of in silico drug screening and in silico target protein screening using a protein-compound affinity matrix calculated by a protein-compound docking software. Our assumption was that the protein-compound binding free energy of a compound could be improved by a linear combination of its docking scores with many different proteins. We proposed two approaches to determine the coefficients of the linear combination. The first approach is based on similarity among the proteins, and the second is a machine-learning approach based on the known active compounds. These methods were applied to in silico screening of the active compounds of several target proteins and in silico target protein screening.     

Kinase-kernel models: accurate in silico screening of 4 million compounds across the entire human kinome

Reliable in silico prediction methods promise many advantages over experimental high-throughput screening (HTS): vastly lower time and cost, affinity magnitude estimates, no requirement for a physical sample, and a knowledge-driven exploration of chemical space. For the specific case of kinases, given several hundred experimental IC(50) training measurements, the empirically parametrized profile-quantitative structure-activity relationship (profile-QSAR) and surrogate AutoShim methods developed at Novartis can predict IC(50) with a reliability approaching experimental HTS. However, in the absence of training data, prediction is much harder. The most common a priori prediction method is docking, which suffers from many limitations: It requires a protein structure, is slow, and cannot predict affinity. (1) Highly accurate profile-QSAR (2) models have now been built for roughly 100 kinases covering most of the kinome. Analyzing correlations among neighboring kinases shows that near neighbors share a high degree of SAR similarity. The novel chemogenomic kinase-kernel method reported here predicts activity for new kinases as a weighted average of predicted activities from profile-QSAR models for nearby neighbor kinases. Three different factors for weighting the neighbors were evaluated: binding site sequence identity to the kinase neighbors, similarity of the training set for each neighbor model to the compound being predicted, and accuracy of each neighbor model. Binding site sequence identity was by far most important, followed by chemical similarity. Model quality had almost no relevance. The median R(2) = 0.55 for kinase-kernel interpolations on 25% of the data of each set held out from method optimization for 51 kinase assays, approached the accuracy of median R(2) = 0.61 for the trained profile-QSAR predictions on the same held out 25% data of each set, far faster and far more accurate than docking. Validation on the full data sets from 18 additional kinase assays not part of method optimization studies also showed strong performance with median R(2) = 0.48. Genetic algorithm optimization of the binding site residues used to compute binding site sequence identity identified 16 privileged residues from a larger set of 46. These 16 are consistent with the kinase selectivity literature and structural biology, further supporting the scientific validity of the approach. A priori kinase-kernel predictions for 4 million compounds were interpolated from 51 existing profile-QSAR models for the remaining >400 novel kinases, totaling 2 billion activity predictions covering the entire kinome. The method has been successfully applied in two therapeutic projects to generate predictions and select compounds for activity testing.     

Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs

Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.     

A new application of diphenylphosphorylazide (DPPA) reagent: convenient transformations of quinolin-4-one, pyridin-4-one and quinazolin-4-one derivatives into the 4-azido and 4-amino counterparts

Herein, we describe a transformation of the oxo-function of a series of quinolin/pyridin/quinazolin-4-ones into 4-azido and thence into 4-amino derivatives in moderate yields by a very short and convenient new procedure using DPPA (diphenylphosphoryl azide) as reagent. A mechanism for this interesting new application of DPPA is suggested based on the identification of some of the intermediates.     

Thermosolvatochromism of betaine dyes revisited: theoretical calculations of the concentrations of alcohol-water hydrogen-bonded species and application to solvation in aqueous alcohols

Solvatochromic data of 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl)phenolate (RB) in aqueous methanol, 1-propanol, 2-propanol, and 2-methyl-2-propanol at 25 degrees C were recalculated by employing a recently introduced model that explicitly considers the presence of 1:1 alcohol-water hydrogen-bonded species, ROH-W, in bulk solution and their exchange equilibria with water and alcohol in the probe solvation microsphere. The thermosolvatochromic behavior of RB in aqueous ethanol was measured in the temperature range from 10 to 60 degrees C; the results thus obtained were treated according to the same model. All calculations require reliable values of Kdissoc, the dissociation constant of the ROH-W species. This was previously calculated from the dependence of the density of the binary solvent mixture on its composition. Through the use of iteration, the volume of the hydrogen-bonded species, VROH-W, and Kdissoc are obtained simultaneously from the same set of experimental data. This approach may be potentially problematic because Kdissoc and VROH-W are highly correlated. Therefore, we introduced the following approach: (i) VROH-W was obtained from ab initio calculations, (ii) these volumes were corrected for the nonideal behavior of the binary solvent mixtures at different temperatures, (iii) corrected VROH-W values were employed as a constant in the equation used to calculate Kdissoc (from density vs binary solvent mixture composition). VROH-W calculated by the COSMO-RS solvation model fitted the density data better than those calculated by the IEFPCM model. In all aqueous alcohols, solvation by ROH-W is favored over that by the two precursor solvents. In aqueous ethanol, a temperature increase resulted in a gradual desolvation of RB, due to a decrease in the hydrogen-bonding of both components of the mixture. The microscopic polarities of ROH-W are much closer to those of the precursor alcohols.     

New synthetic routes to the kainoids: a synthesis of kainic acid and its analogues

New approaches to the synthesis of kainic acid and its analogues are presented. Two distinctly different approaches are described; the former utilised an intermolecular nitrile oxide addition to a homochiral substrate to furnish epikainate models and the second utilised amino acid chemistry to secure kainic acid.     

The direct catalytic asymmetric alpha-aminooxylation reaction: development of stereoselective routes to 1,2-diols and 1,2-amino alcohols and density functional calculations

Proline-catalyzed direct asymmetric alpha-aminooxylation of ketones and aldehydes is described. The proline-catalyzed reactions between unmodified ketones or aldehydes and nitrosobenzene proceeded with excellent diastereo- and enantioselectivities. In all cases tested, the corresponding products were isolated with >95 % ees. Methyl alkyl ketones were regiospecifically oxidized at the methylene carbon atom to afford enantiomerically pure alpha-aminooxylated ketones. In addition, cyclic ketones could be alpha,alpha'-dioxidized with remarkably high selectivity, furnishing the corresponding diaminooxylated ketones with >99 % ees. The reaction mechanism of the proline-catalyzed direct asymmetric alpha-aminooxylation was investigated, and we performed density functional theory (DFT) calculations in order to investigate the nature of the plausible transition states further. We also screened other organocatalysts for the asymmetric alpha-oxidation reaction and found that several proline derivatives were also able to catalyze the transformation with excellent enantioselectivities. Moreover, stereoselective routes for the synthesis of monoprotected vicinal diols and hydroxyketones were found. In addition, short routes for the direct preparation of enantiomerically pure epoxides and 1,2-amino alcohols are presented. The direct catalytic alpha-oxidation is also a novel route for the stereoselective preparation of beta-adrenoreceptor antagonists.     

Mechanism of gas-phase aldose-ketose isomerization: A study using tandem mass spectrometry and theoretical calculations

Fast-atom bombardment tandem mass spectrometry and the semiempirical molecular orbital method were used to investigate the mechanism of gas-phase aldose-ketose isomerization process in lithiated 1,3 linked disaccharide isomers. Both the 1,3 hydrogen shift and hydride transfer mechanisms were investigated. Our experimental and theoretical calculations support the latter. The hydride transfer mechanism in these lithium-coordinated systems is similar to the xylose isomerase catalyzed aldose-ketose isomerization.     

Towards an insight on the photoluminescence of disordered CaWO4 from a joint experimental and theoretical analysis

A joint experimental and theoretical study has been carried out to rationalize for the first time the photoluminescence (PL) properties of disordered CaWO₄ (CWO) thin films. From the experimental side, thin films of CWO have been synthesized following a soft chemical processing, their structure has been confirmed by X-ray diffraction data and corresponding PL properties have been measured using the 488 nm line of an argon ion laser. Although we observe PL at room temperature for the crystalline thin films, the structurally disordered samples present much more intense emission. From the theoretical side, first principles quantum mechanical calculations, based on density functional theory at B3LYP level, have been employed to study the electronic structure of a crystalline (CWO-c) and asymmetric (CWO-a) periodic model. Electronic properties are analyzed in the light of the experimental results and their relevance in relation to the PL behavior of CWO is discussed. The symmetry breaking process on going from CWO-c to CWO-a creates localized electronic levels above the valence band and a negative charge transfer process takes place from threefold, WO₃, to fourfold, WO₄, tungsten coordinations. The correlation of both effects seems to be responsible for the PL of amorphous CWO.     

Diradical cyclization methodologies. Model studies probing the application of photoinduced-electron transfer processes in synthetic routes to the protoberberine and spirobenzyl isoquinoline alkaloids

Model studies have demonstrated that diradical cyclization processes, promoted by excited state electron transfer-desilylation pathways, serve as novel methods for construction of ring systems found in members of the protoberberine and spirobenzyl isoquinoline alkaloid families.     

Asymmetric routes towards polyfunctionalized pyrrolidines: application to the synthesis of alkaloid analogues

The Mukaiyama aldol type condensation of t-butyldimethylsilyloxypyrrole 1b with methyl 2-formylbenzoate furnished the aldol adduct 9 with high yield and complete stereoselectivity. An erythro (anti) configuration was established (X-ray) in sharp contrast with the reaction of 1b with aliphatic aldehydes. Simple chemical transformations were used to transform 9 into original phthalidopyrrolidine compound analogous of bicuculline alkaloids.     

Stereochemical studies on germacrenes: an application of molecular mechanics calculations

Molecular mechanics calculations are successfully carried out to evaluate relative stabilities of each conformation of germacrene-A ($\text{1}$), germacrene-B ($\text{2}$) and hedycaryol ($\text{3}$) in their ground states and transition states. Thus, the calculation results on each transition state model indicate that the elements are formed from the corresponding germacrenes through the most stable transition states (CC), regardless of the most stable conformers in each ground state.     

Synthesis of 1-aminoimidazolidin-4-one and 1-aminoimidazolidin-2-one based compounds: an interesting divergence in methodology

An examination of the methods required for the amination of 2- and 4-imidazolidinones is described.     

Antioxidants and stabilizers: Part XCVI—Antioxidant behaviour of 2,6-di-tert-butyl-4-(4-phenylamino-phenylimino)2,5-cyclohexadiene-1-one

In the autoxidation of squalene (rubber model) the title compound (I) first behaves as an effective antioxidant which, however, gradually loses its efficiency in the course of autoxidation without being destroyed. This behaviour is caused by a reaction in which radical (III), derived from antioxidant (I), reacts with the hydrogen atom in the oxidation products of squalene. The hydrogen atom is not that of the hydroperoxide group. In the reaction, (I) is regenerated and an active radical is formed from the substrate which continues the oxidation. Oxidation of (I) with lead dioxide gave rise to the dimer of the radical (III).     

Selection of in silico drug screening results for G-protein-coupled receptors by using universal active probes

We developed a new protocol for in silico drug screening for G-protein-coupled receptors (GPCRs) using a set of "universal active probes" (UAPs) with an ensemble docking procedure. UAPs are drug-like compounds, which are actual active compounds of a variety of known proteins. The current targets were nine human GPCRs whose three-dimensional (3D) structures are unknown, plus three GPCRs, namely β(2)-adrenergic receptor (ADRB2), A(2A) adenosine receptor (A(2A)), and dopamine D3 receptor (D(3)), whose 3D structures are known. Homology-based models of the GPCRs were constructed based on the crystal structures with careful sequence inspection. After subsequent molecular dynamics (MD) simulation taking into account the explicit lipid membrane molecules with periodic boundary conditions, we obtained multiple model structures of the GPCRs. For each target structure, docking-screening calculations were carried out via the ensemble docking procedure, using both true active compounds of the target proteins and the UAPs with the multiple target screening (MTS) method. Consequently, the multiple model structures showed various screening results with both poor and high hit ratios, the latter of which could be identified as promising for use in in silico screening to find candidate compounds to interact with the proteins. We found that the hit ratio of true active compounds showed a positive correlation to that of the UAPs. Thus, we could retrieve appropriate target structures from the GPCR models by applying the UAPs, even if no active compound is known for the GPCRs. Namely, the screening result that showed a high hit ratio for the UAPs could be used to identify actual hit compounds for the target GPCRs.     

Analytical chemistry of synthetic routes to psychoactive tryptamines. Part I. Characterisation of the Speeter and Anthony synthetic route to 5-methoxy-N,N-diisopropyltryptamine using ESI-MS-MS and ESI-TOF-MS

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a new psychoactive tryptamine derivative, has been synthesised by the Speeter and Anthony procedure. This synthetic route was characterised by ESI-MS-MS, ESI-TOF-MS and NMR. Side products have been identified as 3-(2-N,N-diisopropylamino-ethyl)-1H-indol-5-ol (5), 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanol (6), 2-(5-methoxy-1H-indol-3-yl)-ethanol (7) and 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanone (8).