СОПРЯЖЕННЫЕ МОДЕЛИ ДЛЯ ОДНОВРЕМЕННОГО ПРЕДСКАЗАНИЯ КОНСТАНТЫ ТАУТОМЕРНОГО РАВНОВЕСИЯ И КОНСТАНТЫ КИСЛОТНОСТИ

Исследование поддержано Министерством образования молодежи и спорта Чешской Республики, соглашение MSMT-5727/2018-2, а также Министерством высшего образования и науки Российской Федерации, соглашение 14.587.21.0049 (уникальный идентификатор проекта RFMEFI58718X0049)

Предсказание функционально-связанных характеристик молекул: модель одновременного предсказания константы равновесия реакций таутомерии и кислотности таутомеров

149-15

Virtual screening identifies broad-spectrum \u3b2-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Bacteria are known to evade \u3b2-lactam antibiotic action by producing \u3b2-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available \u3b2-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors

Chemical modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2h-benzo[d]imidazole-2-one scaffold as a novel NLRP3 inhibitor

In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules

Tautomerism in large databases

We have used the Chemical Structure DataBase (CSDB) of the NCI CADD Group, an aggregated collection of over 150 small-molecule databases totaling 103.5 million structure records, to conduct tautomerism analyses on one of the largest currently existing sets of real (i.e. not computer-generated) compounds. This analysis was carried out using calculable chemical structure identifiers developed by the NCI CADD Group, based on hash codes available in the chemoinformatics toolkit CACTVS and a newly developed scoring scheme to define a canonical tautomer for any encountered structure. CACTVS’s tautomerism definition, a set of 21 transform rules expressed in SMIRKS line notation, was used, which takes a comprehensive stance as to the possible types of tautomeric interconversion included. Tautomerism was found to be possible for more than 2/3 of the unique structures in the CSDB. A total of 680 million tautomers were calculated from, and including, the original structure records. Tautomerism overlap within the same individual database (i.e. at least one other entry was present that was really only a different tautomeric representation of the same compound) was found at an average rate of 0.3% of the original structure records, with values as high as nearly 2% for some of the databases in CSDB. Projected onto the set of unique structures (by FICuS identifier), this still occurred in about 1.5% of the cases. Tautomeric overlap across all constituent databases in CSDB was found for nearly 10% of the records in the collection

The Development and Applications of the HINT Scoring Function: Exploring Colchicine-Site Anticancer Agents and Tautomerism

The overall aim of this work was to apply HINT, an empirical scoring function based on the understanding of hydrophobicity, to analyze and predict the binding affinities and biological activities of colchicine-site anticancer agents. The second, concurrent aim was to improve the scoring function by incorporating tautomerism within the modeling process. Our belief is that proper evaluation of tautomeric forms for small molecules will improve performance of virtual screening. The novel pyrrole-based compounds targeting the colchicine site were docked into the receptor using HINT as a rescoring function. Two distinct binding modes dictated by the size and shape of a subpocket were predicted to differentiate the highly active compounds from the weak ones. Of the residues predicted to participate in binding for the active binding mode, Cys241β was revealed to form a weak but critical hydrogen bond with the ligand. A larger collection of colchicine-site agents, biologically tested in the same laboratory including our pyrrole-based compounds were subject to 3D quantitative structure-activity relationship (QSAR) study. Using results on docking the pyrrole compounds as a guide, relative binding poses and QSAR models were built to facilitate ligand design and optimization. A new 3D modeling approach was introduced to visually highlight the unique features of highly active compounds and the commonality of all compounds in the dataset using HINT maps and successfully tested on the colchicine-site agents. These results will provide valuable guidance in the future design and development of new colchicine-site agents. To incorporate tautomerism within HINT, we proposed and developed two workflow approaches: a general search tool using a simple and intuitive algorithm analyzing hydrogen shift patterns to identify and enumerate tautomeric structures, and a database that contains commonly observed tautomeric structures. The first approach was designed for small-scale docking studies and the second approach was designed for large-scale virtual screening. The tautomer module in HINT will give more accurate modeling results when the compound encountered is able to tautomerize

Theory of Aqueous Solvation: Uninterrupted, Cyclic Hydrogen-Bonding Essential for Accurate Keto-Enol Energies and Grotthuss Tautomerism of Acetone

Keto-enol tautomerization (KET) is a fundamental process impacting a range of molecular phenomena in organic and biochemistry. However, the accurate computation of solution-phase KET energies remains a challenge, even for prototypical acetone. In Part I, keto-enol tautomers of acetone were incorporated into solvent clusters that interact via uninterrupted, cyclic hydrogen-bonding (UCHB) networks. An empirical model was created to predict accurate KET energies, Etaut, of simple carbonyl compounds. Based on the availability of experimental data and structural simplicity, acetone was selected as a prototype. A discrete-continuum strategy was employed – accounting simultaneously for local noncovalent interactions and bulk-phase effects – wherein acetone, bound to water clusters of size (H2O)n n = 1–4, was paired with implicit solvent, represented by the polarized continuum model (PCM). Geometry optimizations and harmonic vibrational frequency calculations were completed using the B3LYP, ωΒ97Χ-D, and M06-2X hybrid density functionals paired with Dunning’s correlation-consistent basis sets cc-pV[D,T]Z with maug-, jul-, and aug- diffuse functions. Results were compared to second-order Møller–Plesset perturbation theory (MP2) and the experimental value of Etaut = -11.36 ± 0.04 kcal/mol determined by spectrophotometric bromination. In the context of the dissertation, chemical accuracy is defined to be 1.0 kcal/mol. When using the pseudo-aromatic solvent model, MP2 predicted Etaut within chemical accuracy using the maug-cc-PVTZ basis set, and all density functionals with maug-cc-pVTZ achieved errors below 1.50 kcal/mol for Etaut. In Part II, the solvent model of tautomerization was extended to transition structure (TS) complexes of acetone and explicit water. The same density functionals and MP2 with the same basis sets were employed. Utilizing the concept of a Grotthuss mechanism to mediate proton transfer, models with a single Grotthuss chain provided reductions in activation energies from 60 kcal/mol to less than 40 kcal/mol while UCHB solvated models provided further reductions to less than 35 kcal/mol. Both the addition of Grotthuss chains and incorporation into UCHB solvent networks were necessary to achieve stabilization. In efforts to model acid-catalyzed tautomerism, an excess proton was added to the UCHB structures at three separate sites on acetone. Inclusion of acetone into a solvent cluster allowed for delocalization of the proton defect along the UCHB network. At the B3LYP/jul-cc-pVDZ level of theory, an activation energy of 21.8 kcal/mol was predicted, accounting for 92% of the experimental value of 23.6 kcal/mol, reported by Kresge and coworkers. Nonetheless, the influence of a cyclic solvent network was essential in allowing redistribution of the proton defect. Incorporation of the carbonyl group on acetone into a solvent network both stabilized the keto and enol forms to achieve chemical accuracy and stabilized the TS of protonated Grotthuss chains to improve agreement with experimental values. Results indicate the necessity of UCHB networks for calculating KET energies and the emergence of a novel mechanism for acid-catalyzed enolization of ketones, namely Grotthuss tautomerism. My dissertation demonstrates the necessity of extending Pople’s diagram of computational chemistry by adding the physical model as a third dimension. In doing so, the new paradigm for computational chemistry forges agreement between computation and experiment and sets the foundation to expand my work to complex organic functionality and ultimately to a generalized theory of aqueous solvation