Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

Guasch, Laura; Yapamudiyansel, Waruna; Peach, Megan L.; Kelley, James A.; Barchi, Joseph J.; Nicklaus, Marc C.

doi:10.1021/acs.jcim.6b00338

Cited by 44 publications

(50 citation statements)

References 28 publications

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“…The vital importance of knowing the tautomeric state in various aspects of the drug design has been underlined by many authors [3][4][5][6][7]. Martin [4] wrote recently that about 21% of molecules in various drug discovery databases are potentially tautomeric [8][9][10], and it is crucially important to know the exact tautomeric state in the different stages of the drug design.…”

Section: Introductionmentioning

confidence: 99%

Favipiravir tautomerism: a theoretical insight

Antonov

2020

Theor Chem Acc

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There is no experimental information about the tautomerism of Favipiravir (T-705). Therefore, its tautomeric state was predicted by using density functional theory in gas phase and in solution (toluene, acetonitrile and water). The results have shown that, in neutral state, the enol form is strongly dominating in both gas phase and solution. The carboxamide group is easily protonated in the presence of acid, which leads to shift of the tautomeric equilibrium toward the keto tautomer. In order to validate the theoretical predictions, 2-hydroxy pyridine and 2-hydroxy pyrazine were also included in the set of studied compounds. The available experimental data about their tautomerism are in very good agreement with the theoretical predictions, which validate the conclusions made for T-705.

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Section: Introductionmentioning

confidence: 99%

Favipiravir tautomerism: a theoretical insight

Antonov

2020

Theor Chem Acc

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“…The ligands (HL 1 –HL 5 ) may be present in one or more of three tautomers: A (enolic form) and B and C (keto forms) (Scheme 2) as previously reported for similar pyrazole ligands bearing carbothioamide or acyl groups at N(1) or C(4). [ 26,27 ] Interestingly, it is proved that the exchange between two tautomers could occur in solid via a prototropy process as well as in solution even with similar rate in some cases. [ 28 ] In this regard, if no prototropy would occur in solid state or being blocked, desmotropy or polymorphism processes are considered a common reason to have two or more tautomers in the crystalline state.…”

Section: Resultsmentioning

confidence: 99%

New pyrazole‐4‐carbothioamide‐based metal complexes: Synthesis, spectral characterization, computational, antimicrobial, and antitumor investigations

Ramadan

Elsamra

Bondock

2020

Applied Organom Chemis

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A series of 5‐hydroxy‐4‐(N‐substituted carbothioamide) pyrazole derivatives (HL1–HL5) and their iron(III), nickel(II), and copper(II) complexes have been synthesized. Structural elucidations of the isolated ligands and their complexes are basically accomplished by FT‐IR, 1H NMR, 13C NMR, UV–Vis, ESR, MS, and thermogravimetric analysis (TGA). The analytical data propose the stoichiometries 1:3 (M:L) for Fe(III) and 2:3 for both Ni(II) and Cu(II) complexes. The spectral data substantiate the bidentate coordination mode for all ligands towards metal ions via S and O atoms of CS of the carbothioamide group at pyrazole‐C4 and OH group at C(5) where deprotonation occurs from the enolic tautomer on chelation. Likewise, bidentate pattern of a bridged acetate group is confirmed in the case of Ni(II) and Cu(II) complexes. The magnetic moment values validate high spin octahedral geometry for Fe(III) complexes whereas the diamagnetic feature of Ni(II) complexes is in conformity with the square planar symmetry of low spin state. ESR spectra of all Cu(II) complexes support their existence in distorted square planar geometry with a considerable electron exchange between two copper ion centers of dinuclear type. TGA and DTG analysis of six complexes display their considerable thermal stability. Besides, the in vitro biological screening effects of some selected compounds are tested against various human pathogen microorganisms. Among the ligands, HL5 exhibits the greatest antibacterial activity against two Gram‐positive species (Bacillus subtilis and Staphylococcus aureus) and one Gram‐negative (Proteus vulgaris) in comparison with gentamicin drug. Furthermore, IC50 values of [Cu2(L5)3(OAc)] complex reveal its significant anticancer activity against the three tumor cell lines HCT‐116, MCF‐7, and HepG‐2 compared with imatinib and cisplatin as positive controls. Finally, the optimized structures of all ligands and their molecular electrostatic potential surfaces are established by utilizing density functional theory (DFT).

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“…We consider here three types of duplicate entries. First, a single molecule can present several protonation states and tautomers, which could become problematic when merging different molecular databases. InChiKey is a robust and efficient method for detecting duplicates, once molecules have been adequately standardized.…”

Section: Methodsmentioning

confidence: 99%

VSPrep: A General KNIME Workflow for the Preparation of Molecules for Virtual Screening

Gally

Bourg

Do³

et al. 2017

Molecular Informatics

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Over the past decades, virtual screening has proved itself to be a valuable asset to identify new bioactive compounds. The vast majority of commonly used techniques can be described in three steps: pre-processing the dataset i. e. small (ligands) and eventually larger (receptors) molecules, execute the method and finally analyse the results. Hence, the preparation of ligands is a critical step for success of commonly used virtual screening approaches such as protein-ligand docking, similarity or pharmacophore search. We present here a new workflow, VSPrep, for the pre-processing of small molecules; it is based on freely accessible tools for academics and is integrated within the KNIME platform. It can be used to perform several chemoinformatics tasks such as molecular database cleaning, tautomer and stereoisomer enumeration, focused library design and conformer generation. Additionally, graphical reports of the results are provided to the user as a convenient analysis tool.

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Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

Cited by 44 publications

References 28 publications

Favipiravir tautomerism: a theoretical insight

Favipiravir tautomerism: a theoretical insight

New pyrazole‐4‐carbothioamide‐based metal complexes: Synthesis, spectral characterization, computational, antimicrobial, and antitumor investigations

VSPrep: A General KNIME Workflow for the Preparation of Molecules for Virtual Screening

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