New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling

Ilin, İvan; Lipets, Elena N.; Сулимов, А. В.; Kutov, Danil; Shikhaliev, Kh. S.; Potapov, A. Yu.; Krysin, M. Yu.; Zubkov, Fedor I.; Sapronova, L. V.; Ataullakhanov, F. I.; Сулимов, В. Б.

doi:10.1016/j.jmgm.2019.03.017

Cited by 20 publications

(15 citation statements)

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“…In our previous work [17,18], derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one (PQ, 1) were found to be perspective FXa inhibitors, with IC50 values in the range of 0.7 to 40 μM. These identified inhibitors represent hybrid molecules consisting of dihydroquinoline (2) [18], pyrrolidinone (3) [19], and rhodanine (4) [20] (see Figure 3), which are known to be active moieties of different inhibitors of coagulation factors. (1) and structural fragments of some known inhibitors of coagulation factors: 1,2-dihydroquinoline (2), pyrrolidinone (3), and rhodanine (4).…”

Section: Design Of Pyrrolo[3 21-ij]quinolin-2(1h)-one-based Derivativesmentioning

confidence: 99%

“…1,2,3,4-Tetrahydroquinolines (5,6) with phenyl and methyl substituents [18,21] as well as 1,2-dihydroquinolines containing N-acetylaminomethyl groups at C 4 (8) [22] (see Figure 4) are also proven to form a structural basis for compounds with anticoagulant activity. Inhibitory activity against factor FXa was also detected for other 1,2,3,4-tetrahydroquinolines [23].…”

Section: Design Of Pyrrolo[3 21-ij]quinolin-2(1h)-one-based Derivativesmentioning

confidence: 99%

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Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

et al. 2020

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Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

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Section: Design Of Pyrrolo[3 21-ij]quinolin-2(1h)-one-based Derivativesmentioning

confidence: 99%

Section: Design Of Pyrrolo[3 21-ij]quinolin-2(1h)-one-based Derivativesmentioning

confidence: 99%

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

et al. 2020

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“…The compounds are small drug-like molecules. Among them there are hydroquinoline derivatives with antibacterial, antifungal, anticoagulant activity [22,25,34,37,38], aminopyrimidines and pyrrolo[3,2,1-ij]quinolin-2-ones, which are factor Xa and protein kinases inhibitors [50,54], various plant growth stimulants of the getarylcarboxylic acid class [63,64].…”

Section: Database and Ligand 3d Structure Preparationmentioning

confidence: 99%

“…SOL was used for CSAR 2011-2012 docking competition with other docking programs Gold, AutoDock, AutoDock Vina, ICMVLS, Glide and others and for two of three target-proteins SOL results are among the best ones [8,53]. SOL is successfully used for development of new inhibitors of several targets with the experimental in vitro confirmation: thrombin [45], urokinase (uPA) [4,55] and the blood coagulation factors Xa and XIa [22,38,54]. SOL is adapted to screen large databases of ligands on Lomonosov supercomputer [62] of M.V.…”

Section: Sol Docking Programmentioning

confidence: 99%

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

2020

JSFI

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Two stages virtual screening of a database containing several thousand low molecular weight organic compounds is performed with the goal to find inhibitors of SARS-CoV-2 main protease. Overall near 41000 different 3D molecular structures have been generated from the initial molecules taking into account several conformers of most molecules. At the first stage the classical SOL docking program is used to determine most promising candidates to become inhibitors. SOL employs the MMFF94 force field, the genetic algorithm (GA) of the global energy optimization, takes into account the desolvation effect arising upon protein-ligand binding and the internal stress energy of the ligand. Parameters of GA are selected to perform the meticulous global optimization, and for docking of one ligand several hours on one computing core are needed on the average. The main protease model is constructed on the base of the protein structure from the Protein Data Bank complex 6W63. More than 1000 ligands structures have been selected for further postprocessing. The SOL score values of these ligands are more negative than the threshold of −6.3 kcal/mol obtained for the native X77 ligand docking. Subsequent calculation of the protein-ligand binding enthalpy by the PM7 quantum-chemical semiempirical method with COSMO solvent model have narrowed down the number of best candidates. Finally, the diverse set of 20 most perspective candidates for the in vitro validation are selected.

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“…Современные тенденции в области разработки препаратов, связанных с фактором свертывания Ха, характеризуются двумя направлениями. С одной стороны, растет число случаев идентификации новых классов прямых ингибиторов фактора Ха, причем чаще всего с использованием методов молекулярного моделирования [52][53][54][55][56]. Примеры некоторых новых ингибиторов, разработанных с помощью компьютерного моделирования, приведены в таблице 2.…”

Section: прямые ингибиторы ключевых факторов свертыванияunclassified

Blood coagulation in the 21st century: existing knowledge, current strategies for treatment and perspective

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Tashchilova

et al. 2020

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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Disorders in the blood coagulation system are the leading cause of death and disability in the modern world. So the search for new drugs that can prevent pathological thrombosis, while not affecting normal hemostasis, becomes more relevant than ever. Recent studies has been a revolution in the understanding of the principles of work and the regulation of blood coagulation. In addition, new, more effective approaches to drug development have now appeared. For example computer simulation methods that can significantly reduce the time and resources spent on the search for new candidate molecules. In the review, the blood clotting system, the molekular mechanisms of thrombosis, the role of blood coagulation factors Xa and XIa, and the urgency of developing new inhibitors of these targets are shown, and the most interesting inhibitors of factors Xa and XIa are presented.

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New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling

Cited by 20 publications

References 32 publications

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

Blood coagulation in the 21st century: existing knowledge, current strategies for treatment and perspective

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