RESUMO
A novel approach to the utilization of nuclear magnetic resonance (NMR) spectroscopy data in the prediction of logD through machine learning algorithms is shown. In the analysis, a data set of 754 chemical compounds, organized into 30 clusters, was evaluated using advanced machine learning models, such as Support Vector Regression (SVR), Gradient Boosting, and AdaBoost, and comprehensive validation and testing methods were employed, including 10-fold cross-validation, bootstrapping, and leave-one-out. The study revealed the superior performance of the Bucket Integration method for dimensionality reduction, consistently yielding the lowest root mean square error (RMSE) across all data sets and normalization schemes. The SVR prediction models demonstrated remarkable computational efficiency and low cost, with the best RMSE value reaching 0.66. Our best model outperformed existing tools like JChem Suite's logD Predictor (0.91) and CplogD (1.27), and a comparison with traditional molecular representations yielded a comparable RMSE (0.50), emphasizing the robustness of our NMR data integration. The widespread availability of NMR data in pharmaceutical and industrial research presents an untapped resource for predictive modeling, highlighting the need for accessible methodologies like ours that complement the analytical toolbox beyond conventional 2D approaches. Our approach, designed to leverage the rich spatial data from NMR spectroscopy, provides additional insights and enriches drug discovery and computational chemistry with a freely accessible tool.
Assuntos
Aprendizado de Máquina , Espectroscopia de Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Inteligência Artificial , Máquina de Vetores de Suporte , Algoritmos , Fenômenos QuímicosRESUMO
In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.
Assuntos
Neuralgia , Receptores Histamínicos H3 , Receptores sigma , Humanos , Histamina , Receptores Histamínicos H3/química , Ligantes , Nociceptividade , Piperazina , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/química , Neuralgia/tratamento farmacológico , Relação Estrutura-Atividade , Receptor Sigma-1RESUMO
As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.
Assuntos
Flúor , Fosfatidilinositol 3-Quinases , Simulação de Acoplamento Molecular , Fluxo de Trabalho , Simulação de Dinâmica MolecularRESUMO
Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, ß, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 µM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kß/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.
RESUMO
Phosphoinositide 3-kinase δ (PI3Kδ), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-a]pyrimidine with IC50 values in the low nanomolar range and high selectivity against the PI3Kδ isoform. CPL302253 (54), the most potent compound of all the structures obtained, with IC50 = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.
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The double Knoevenagel condensation of 1,4-dibenzoyloxyanthraquinone with methyl esters of arylacetic acids affords a series of compounds based upon a previously unknown 1,8-dioxa-benzo[e]pyrene-2,7-dione heterocyclic core. The aryl groups incorporated in the 3- and 6-positions can be oxidatively coupled to the π-expanded backbone to produce a further new heterocyclic core: 1,10-dioxa-dibenzo[dj]coronene-2,9-dione. The intriguing optical properties of these π-expanded coumarin derivatives are discussed and rationalized through quantum chemical calculations. The broad absorption bands of 1,8-dioxa-benzo[e]pyrene-2,7-dione-based dyes are attributed to both HOMO-1âLUMO and HOMOâLUMO transitions, which have a similar energy. Weakly coupled electron-donating aryl substituents result in a moderate bathochromic shift of both the absorption and emission by 30-60â nm in toluene. The emissive properties of these compounds are in part determined by the oscillator strength of the main transition, lifetimes of the excited state, and by the energy match of the excited state with a triplet state of a similar energy. The 1,10-dioxa-dibenzo[dj]coronene-2,9-dione displays a much smaller Stokes shift, yet a markedly increased fluorescence quantum yield of 90 % owing to the increased rigidity compared with the 1,8-dioxa-benzo[e]pyrene-2,7-dione core.
RESUMO
Nystatin A1 , a polyene macrolide antifungal antibiotic, in a slightly basic or acidic solution undergoes an intramolecular transformation, yielding a structural isomer, the translactonization product, iso-nystatin A1 with lactone ring diminished by two carbon atoms. Structural evidence is provided by advanced NMR and Mass Spectrometry (MS) studies. Molecular dynamics simulations and quantum mechanics calculations gave the insight into the course and mechanism of the transformation and its effect on the conformation of the subject molecule. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Antifúngicos/química , Nistatina/análogos & derivados , Nistatina/química , Cromatografia Líquida de Alta Pressão , Isomerismo , Lactonas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Conformação Molecular , Simulação de Dinâmica MolecularRESUMO
New synthetic methods leading towards π-expanded heterocycles are sought after mainly due to their promising opto-electronic properties. Subjecting 1,5,9,10-tetramethoxyanthracene to the modern Duff reaction conditions led to the formation of a compound possessing the 2-azabenzoanthrone (dibenzo[de,h]isoquinolin-7-on) skeleton instead of the expected dialdehyde. This non-typical course of reaction can be rationalized by the double electrophilic aromatic substitution at two neighboring electron-rich positions of anthracene followed by oxidation of the resulting intermediate to form a pyridine ring. Optical studies supported by the quantum chemistry calculations indicated the lack of excited-state intramolecular proton transfer (ESIPT); for energy reasons, only one tautomeric form, with a hydrogen atom bonded to one of the two nearby oxygen atoms, was populated in the electronic ground S0 and in the excited S1 states. Nonradiative depopulation of the S1 state proceeded via internal conversion stimulated by the presence of the low frequency vibrational modes. Our serendipitous discovery represents the most complex case of rearrangement of aromatic compounds under Duff reaction conditions and could help to design analogous processes. At the same time this is the simplest method for the synthesis of derivatives of 2-azabenzoanthrone.
RESUMO
Previously unknown, vertically linked heterocycles comprised of benzofuran and iminocoumarin moieties have been synthesized directly from 1,5-dibenzoyloxyanthraquinone and arylacetonitriles via double Knoevenagel condensation followed by formal HCN elimination. The structural assembly of fully conjugated, electron-rich benzofuran and electron-deficient iminocoumarin is responsible for the strongly polarized nature of these heterocycles which translates into their polarity-sensitive fluorescence.
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Seven new oligomeric complexes of 4,4'-bipyridine; 3,3'-bipyridine; benzene-1,4-diamine; benzene-1,3-diamine; benzene-1,2-diamine; and benzidine with rhodium tetraacetate, as well as 4,4'-bipyridine with molybdenum tetraacetate, have been obtained and investigated by elemental analysis and solid-state nuclear magnetic resonance spectroscopy, (13)C and (15)N CPMAS NMR. The known complexes of pyrazine with rhodium tetrabenzoate, benzoquinone with rhodium tetrapivalate, 4,4'-bipyridine with molybdenum tetrakistrifluoroacetate and the 1 : 1 complex of 2,2'-bipyridine with rhodium tetraacetate exhibiting axial-equatorial ligation mode have been obtained as well for comparison purposes. Elemental analysis revealed 1 : 1 complex stoichiometry of all complexes. The (15)N CPMAS NMR spectra of all new complexes consist of one narrow signal, indicating regular uniform structures. Benzidine forms a heterogeneous material, probably containing linear oligomers and products of further reactions. The complexes were characterized by the parameter complexation shift Δδ (Δδ = δcomplex - δligand). This parameter ranged from around -40 to -90 ppm in the case of heteroaromatic ligands, from around -12 to -22 ppm for diamines and from -16 to -31 ppm for the complexes of molybdenum tetracarboxylates with 4,4'-bipyridine. The experimental results have been supported by a density functional theory computation of (15)N NMR chemical shifts and complexation shifts at the non-relativistic Becke, three-parameter, Perdew-Wang 91/[6-311++G(2d,p), Stuttgart] and GGA-PBE/QZ4P levels of theory and at the relativistic scalar and spin-orbit zeroth order regular approximation/GGA-PBE/QZ4P level of theory. Nucleus-independent chemical shifts have been calculated for the selected compounds.