New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation

Tashchilova, Anna; Подоплелова, Н. А.; Сулимов, А. В.; Kutov, Danil; Ilin, İvan; Panteleev, Mikhail A.; Shikhaliev, Kh. S.; Медведева, С. М.; Novichikhina, N. P.; Potapov, A. Yu.; Сулимов, В. Б.

doi:10.3390/molecules27041234

Cited by 12 publications

(11 citation statements)

References 51 publications

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“…We see that all these 16 ligands belong to 14 different chemical classes. In terms of novelty, only one compound, 224836 , contains scaffold that is similar to a central core of confirmed pyrrolo-dihydroquinoline-based factor XIIa inhibitors with micromolar activity and published in [ 34 ]. The chemical classes of the rest compounds are novel and different from chemical classes of published experimentally confirmed inhibitors of factor XIIa [34-36].…”

Section: Resultsmentioning

confidence: 99%

Supercomputer Search for the New Inhibitors of the Coagulation Factor XIIa

Сулимов

Kutov²,

Ilin³

et al. 2022

Lobachevskii J Math

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A virtual structure-oriented screening of candidates for inhibitors of blood coagulation factor XIIa was carried out. This coagulation factor is one of the most promising therapeutic targets for the development of anticoagulants without disturbing normal hemostasis. The screening was carried out in the database of organic compounds of the Voronezh State University, consisting of more than 19 thousand molecules. At the first stage of virtual screening, ligands were positioned in the active center of factor XIIa using the SOL docking program. At the second stage, for the best ligands, the protein-ligand binding enthalpy was calculated using the MOPAC program and the PM7 quantum-chemical method, taking into account the solvent in the COSMO continuum model. All calculations were carried out using the supercomputing resources at Lomonosov Moscow State University. In total, more than 30 thousand ligand conformers are docked, and for more than 400 of the best of them, the protein-ligand binding enthalpy was calculated. 16 compounds are selected as the most promising candidates for subsequent in vitro testing of their ability to inhibit factor XIIa.

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Section: Resultsmentioning

confidence: 99%

Supercomputer Search for the New Inhibitors of the Coagulation Factor XIIa

Сулимов

Kutov²,

Ilin³

et al. 2022

Lobachevskii J Math

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“…[23,24] The recent application of the SOL program for drug design can be found in. [20,26,27] The second stage of the virtual screening was a semiempirical quantum-chemical post-processing. The main purpose of this procedure was to more accurately predict the binding affinity for compounds that show the best results when docked.…”

Section: Virtual Screeningmentioning

confidence: 99%

“…Recently four micromolar factor XIIa inhibitors were identified in our laboratory by virtual screening of the focused library of 59 compounds. [20] Among found actives, the best compound had 3-arylcoumarin core and showed IC 50 of 7.85 μM and good selectivity over factor Xa and factor XIa. To better explore chemical space and find additional chemotypes, we performed virtual screening of 19 000 drug-like molecules in the study [21] and reported 16 potential factor XIIa inhibitors.…”

Section: Introductionmentioning

confidence: 96%

“…They managed to improve selectivity profile over related off‐targets. Recently four micromolar factor XIIa inhibitors were identified in our laboratory by virtual screening of the focused library of 59 compounds [20] . Among found actives, the best compound had 3‐arylcoumarin core and showed IC 50 of 7.85 μM and good selectivity over factor Xa and factor XIa.…”

Section: Introductionmentioning

confidence: 99%

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Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post‐processing

Ilin

Подоплелова

Сулимов

et al. 2022

Molecular Informatics

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Antithrombotic agents based on factor XIIa inhibitors can become a new class of drugs to manage conditions associated with thrombosis. Herein, we report identification of two novel classes of factor XIIa inhibitors. The first one is triazolopyrimidine derivatives designed on the basis of the literature aminotriazole hit and identified using virtual screening of the focused library. The second class is a spirocyclic furo [3,4-c]pyrrole derivatives identified by virtual screening of a large chemical library of drug-like compounds performed in a previous study but confirmed in vitro here. In both cases, the prediction of inhibitory activity is based on the score of the SOL docking program, which uses the MMFF94 force field to calculate the binding energy. For the best ligands selected in virtual screening of the large chemical library, postprocessing with the PM7 semiempirical quantum-chemical method was used to calculate the enthalpy of protein-ligand binding to prioritize 16 compounds for testing in enzymatic assay, and one of them demonstrated micromolar activity. For triazolopyrimidine library, 21 compounds were prioritized for the testing based on docking scores, and visual inspection of docking poses. Of these, 4 compounds showed inhibition of factor XIIa at 30 μM.

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“…Therefore, the design of hybrid or chimeric compounds in the structure of which the dithiol ring is combined with another heterocyclic fragment (for example, azaheterocycle) with a certain pharmacological activity is of current interest. Among azaheterocycles, 2,2-disubstituted-1,2-dihydroquinolines functionalized at the benzene ring and/or the nitrogen atom (DHQ), which have a wide spectrum of biological activity-anticoagulant, antimalarial, antiparasitic, antibacterial, antidiabetic, anti-inflammatory, neuroprotective, and hepatoprotective activity-are of particular interest [27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors

Медведева

Shikhaliev

2022

Molecules

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This study represents the design and synthesis of a new set of hybrid and chimeric derivatives of 4,5-dihydro-4,4-dimethyl-1H-[1,2]dithiolo[3,4-c]quinoline-1-thiones, the structure of which the tricyclic fragment linearly bound or/and condensed with another heterocyclic fragment. Using the PASS Online software, among the previously synthesized and new derivatives of 1,2-dithiolo[3,4-c]quinoline-1-thione we identified 12 substances with pleiotropic activity, including chemoprotective and antitumor activity. All the synthesized derivatives were screened for their inhibitory assessment against a number of kinases. Compounds which exhibited prominent inhibition percentage in cells (>85%) were also examined for their inhibitory efficiency on human kinases via ELISA utilizing sorafenib as a reference standard to estimate their IC50 values. It was revealed that compounds 2a, 2b, 2c, and 2q displayed a significant inhibition JAK3 (IC50 = 0.36 μM, 0.38 μM, 0.41 μM, and 0.46 μM, respectively); moreover, compounds 2a and 2b displayed excellent activities against NPM1-ALK (IC50 = 0.54 μM, 0.25 μM, respectively), against cRAF[Y340D][Y341D], compound 2c showed excellent activity, and compound 2q showed weak activity (IC50 = 0.78 μM, 5.34 μM, respectively) (sorafenib IC50 = 0.78 μM, 0.43 μM, 1.95 μM, respectively). Thus, new promising preferred structures for the creation of drugs for the treatment of cancer and other multifactorial diseases in the future have been found.

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New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation

Cited by 12 publications

References 51 publications

Supercomputer Search for the New Inhibitors of the Coagulation Factor XIIa

Supercomputer Search for the New Inhibitors of the Coagulation Factor XIIa

Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post‐processing

Synthesis of 4,5-Dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione Derivatives and Their Application as Protein Kinase Inhibitors

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