Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches

Lagos, Carlos F.; Segovia, Gerardine F; Núñez-Navarro, Nicolás; Faúndez, Mario; Zacconi, Flavia

doi:10.3390/molecules22101588

Cited by 10 publications

(7 citation statements)

References 47 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…By using SensoLyte ® 520 Factor Xa Assay Kit "Fluorimetric" FXa (bovine isolated enzyme) inhibition was measured. Upon FXa protease cleavage, this substrate generates the Rh110 (rhodamine 110) as free fluorophore, which can be detected at excitation/emission of 490 nm/520 nm, where the following values of inhibition FXa percentage and IC 50 from the representative compounds of each series (compounds 6-38, Table 9), as well as for all final 1H-1,2,3-triazole derivatives [68,99] were obtained.…”

Section: Fxa Inhibition In Vitro Assaymentioning

confidence: 99%

See 1 more Smart Citation

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

et al. 2020

View full text Add to dashboard Cite

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (µ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.

show abstract

Section: Fxa Inhibition In Vitro Assaymentioning

confidence: 99%

“…Hence, in our continuous search for decisive FXa inhibitors, several approaches in designing synthesis and characterization novel FXa inhibitors [68] have been undertaken.…”

Section: Introductionmentioning

confidence: 99%

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A number of molecular modeling and computer-aided design studies have been reported for both FXa [ 15 , 16 , 17 ] and FIXa [ 18 , 19 ] along with some structure based investigations [ 20 ]. As per the therapeutic strategy described above, i.e., selectively inhibiting the intrinsic pathway without any change in the extrinsic pathway and the common pathway, FIXa is considered as the strategic therapeutic target for this study.…”

Section: Introductionmentioning

confidence: 99%

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Kundu

2021

Molecules

View full text Add to dashboard Cite

Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein–ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than −8.0 kcal/mol in the FIXa-grids and higher than −7.5 kcal/mol in the FXa-grids.

show abstract

“…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

Подоплелова

Сулимов

Tashchilova

et al. 2020

Voprosy gematologii/onkologii i immunopatologii v pediatrii

View full text Add to dashboard Cite

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.

show abstract

Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches

Cited by 10 publications

References 47 publications

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

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

Contact Info

Product

Resources

About