Contemporary developments in the discovery of selective factor Xa inhibitors: A review

Patel, N. K.; Patel, Dushyant V.; Murumkar, Prashant R.; Yadav, Mange Ram

doi:10.1016/j.ejmech.2016.05.039

Cited by 46 publications

(41 citation statements)

References 121 publications

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“…In particular, we compare chloro‐ versus methyl‐substituted ligands targeting factor Xa (fXa), a key enzyme in the blood coagulation cascade. Ligands of this general class have recently been introduced as effective therapeutic agents for the prevention of deep vein thrombosis and stroke. A key to the development of these orally available ligands was the introduction of a neutral ligand moiety targeting the negatively charged S1 pocket of fXa.…”

Section: Figurementioning

confidence: 99%

The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

Parrish

Sitkoff

Cheney

et al. 2017

Chemistry A European J

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The study of noncovalent interactions, notably including drug-protein binding, relies heavily on the language of localized functional group contacts:h ydrogen bonding, p-p interactions, CH-p contacts, halogen bonding, etc. Applyingt he state-of-the-art functional group symmetry-adapted perturbation theory (F-SAPT) to an important question of chloro versus methyl aryl substitution in factor Xa inhibitor drugs, we find that al ocalized contact model provides an incorrect picture for the origin of the enhancement of chloro-containing ligands. Instead, the enhancement is found to originate from many intermediate-range contacts distributed throughout the binding pocket, particularly including the peptideb onds in the protein backbone. The contributionsf rom these contacts are primarily electrostatic in nature,b ut requirea bi nitio computations involvingn early the full drug-protein pocket system to be accurately quantified.Computational drug design,d espite severaln otable achievements, [1] remains af rontier area for theoretical chemistry,w ith numerous unresolved challenges. Formally,t he disciplines of electronic structure theory and statistical mechanics can provide arbitrarily accurate predictions of desired observables, e.g.,o ft he ligand-protein binding energy DG bind .H owever,i n practice, the computational effort required to accurately encapsulate the physics for these observablesi si ntractable. [2] For example, to accurately compute DG bind for ag iven ligand-protein system,one must implicitly or explicitly capture the contributions from the gas-phaseinteraction energy DE int ,solventeffects, including the desolvation penalties of the ligand and binding pocket, and the dynamic vibrational and conformational corrections. [2,3] Moreover, all of thesee ffects shouldb em odeled using an ab initio qualityp otential surface. Though much progress toward accurate characterization of DG bind has been made along the lines of quantum chemistry [4] and free energy perturbation theory, [3,5,6] direct quantification of this metric remains elusive.An alternative approach involves startingf rom ak nown and well-characterized ligand-protein system, and then proposing substitutions to the ligand to enhance the binding affinity.T his approachi so stensibly simpler, as one only needs to predict the binding energyd ifference DDG bind accurately.F or simple substitutions involving similarp olarities, the differences in ligand desolvation penalties and dynamical contributionsm ay be small relative to DDG bind .I ns uch cases, DDG bind will be largely governed by the differenceo ft he interaction energy DDE int between the ligand and the protein, and it suffices to characterize the latter quantity to predict, at least qualitatively, the substituted ligand's affinity.N ote that there exist many cases in which the differentiald esolvation penalties and dynamicalc ontributions are not small, and require direct computation of DDG bind for an accurate result (e.g.,i nt he case of boundl igandsw hich are partially exposed ...

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Section: Figurementioning

confidence: 99%

The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

Parrish

Sitkoff

Cheney

et al. 2017

Chemistry A European J

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“…Idarucizumab was developed as an antidote for dabigatran to avoid hemorrhage via the reversal of anticoagulant effects. This antidote has a 300-fold stronger binding affinity to thrombin than dabigatran, and it can avoid critical bleeding secondary to anticoagulation [2, 10, 15, 16]. Recent reports also proposed a heparin-induced thrombocytopenia (HIT) mechanism which demonstrates a relationship of pathogenic antibodies and the complex generation between platelet factor 4 (PF4) and heparin [17].…”

Section: Discussionmentioning

confidence: 99%

“…3a). Additionally, the hydrophobic cores, such as benzimidazole and pyridine, are an important scaffold acting as a pharmacophore for its anticoagulant activity [2, 11]. The carboxylate group in dabigatran can generate hydrogen bonds with free water and other molecules that help to release dabigatran.…”

Section: Discussionmentioning

confidence: 99%

“…Thromboembolic disorders are a major cause of myocardial infarction, venous thromboembolism, and stroke secondary to hypercoagulation [1, 2]. Warfarin, a vitamin K antagonist, and heparin, an indirect thrombin inhibitor, were used for many years to achieve anticoagulation, although, these treatments can occasionally cause bleeding given their narrow therapeutic window and non-specific interactions [3, 4].…”

Section: Introductionmentioning

confidence: 99%

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Thrombocytopenia induced by dabigatran: two case reports

et al. 2017

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BackgroundVitamin K inhibitors (e.g. warfarin) and indirect thrombin inhibitors (e.g. heparin) are widely used to prevent thromboembolic disorders (e.g. myocardial infarction, venous thromboembolism, and stroke). These agents have been mainstays of anticoagulation for people older than 60 years. However, their administration is associated with a risk of bleeding and requires careful monitoring of patients. Novel oral anticoagulants (NOACs), such as dabigatran, are significantly safer in preventing thromboembolism than warfarin and heparin (sporadically causes thrombocytopenia) and are more specific for their target protein, thrombin. The major advantage of dabigatran, a direct thrombin inhibitor, is that it reversibly inhibits both free and clot-bound thrombin by tight binding affinity and the predictable pharmacodynamic effect. A few studies, however, reported that dabigatran can cause thrombocytopenia, although the underlying mechanism remains unclear. Thus, an antidote for dabigatran was developed to prevent thrombocytopenia.Case presentationIn this report, we discuss two cases of thrombocytopenia and purpura after dabigatran treatment. A 73-year-old man showed hemorrhagic necrotic skin lesions on his neck and right hand. He was administered dabigatran (220 mg/day) for cerebral infarction for three days and his platelet count decreased abruptly (6000/μL). This suggested that dabigatran had caused thrombocytopenia and purpura; therefore, dabigatran administration was discontinued. The results of a blood test, performed 14 days after stopping dabigatran treatment, showed that the platelet count had recovered to the normal range of more than 150,000/μL. A 75-year-old woman had taken warfarin continuously for 8 years. However, she had a new cerebral infarction. Therefore, warfarin treatment was replaced with dabigatran (300 mg/day). Her platelet count decreased (41,000/μL) significantly and dabigatran treatment was discontinued. The blood test results show that platelet counts gradually recovered to the normal range.ConclusionsDabigatran application may cause bleeding; therefore, careful monitoring during dabigatran treatment is required to prevent thrombocytopenia. An explanation is that the interaction of dabigatran with thrombin, because of its strong binding affinity, may cause the observed thrombocytopenia.

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“…In recent years, there are many types of treatments for MI, such as reducing incidence of coronary atherosclerosis [6], antithrombotic therapy including vitamin K antagonists [7], antiplatelet therapy with low-dose aspirin [8], and clopidogrel [9]. In addition, invasive vascular reconstruction is widely used, which improves coronary perfusion, such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) [10].…”

Section: Introductionmentioning

confidence: 99%

Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence

Zhang

Zhu

et al. 2017

Oxidative Medicine and Cellular Longevity

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Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction.

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Contemporary developments in the discovery of selective factor Xa inhibitors: A review

Cited by 46 publications

References 121 publications

The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

The Surprising Importance of Peptide Bond Contacts in Drug–Protein Interactions

Thrombocytopenia induced by dabigatran: two case reports

Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence

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