Comparative molecular field analysis and comparative molecular similarity indices analysis studies of α-ketothiazole arginine analogues inhibitors of coagulation factor XIa

Mercado, Jairo; Gómez, Harold A.; Vivas‐Reyes, Ricardo

doi:10.1039/c0nj00704h

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…CoMFA and CoMSIA are two general applied tools of 3D-QSAR [26]. These methods are based on descriptors of 3D structures to analyze the different contributions of steric (S), electrostatic (E), hydrophobic (H), H-bond donor (HD), and H-bond acceptor (HA) fields [32,33]. These descriptors are directly related to the atomic properties of compounds and the spatial geometry of molecules.…”

Section: Comfa and Comsia Modelsmentioning

confidence: 99%

Rational design of novel phenol ether derivatives as non-covalent proteasome inhibitors through 3D-QSAR, molecular docking and ADMET prediction

Yuan,

Ji,

Sun

et al. 2023

Explor Drug Sci

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Aim: The purpose of this paper is to use different structures and ligand-based drug design methods properly to provide theoretical guidance for the design of novel non-covalent proteasome inhibitors, and conduct theoretical analysis of the binding interaction mode between receptors and ligands. At the same time, the pharmacokinetic (PK) prediction, drug-likeness, and synthesis prediction were made for the screened novel drugs. Therefore, potentially attractive non-covalent proteasome inhibitors with low toxicity could be found as anticancer drugs. Methods: In this work, computer-aided drug design methods, including quantitative structure-activity relationship (QSAR), molecular docking, absorption, distribution, metabolism, excretion, and toxicology (ADMET) prediction, and drug-likeness prediction methods were performed. Results: In this study, the structure-activity relationship (SAR) of a series of non-covalent proteasome inhibitors were studied and the optimal comparative molecular field analysis (CoMFA; Q2 = 0.574, r2 = 0.999, r2pred = 0.755) and comparative molecular similarity indices analysis (CoMSIA)-SEHA (Q2 = 0.584, r2 = 0.989, r2pred = 0.921) models were obtained. According to the results of the QSAR model, some vital clues were found that would effectively enhance the biological activity of the compound. Based on these clues, 24 novel non-covalent proteasome inhibitors (D01–D24) were finally designed and screened. While the binding models between proteasome [protein data bank (PDB) code: 3MG6] and three representative compounds (15, 20, and D24) were also analyzed by using the molecular docking method. The results suggested that hydrogen bond and hydrophobic interaction played a key role in binding interaction between the receptor and ligand. In addition, the results of ADMET prediction indicated that the new designed compounds had reasonable PK parameters and drug-like properties. Conclusions: These statistical results can provide theoretical guidance for structural optimization, design, and synthesis of more effective non-covalent proteasome inhibitors in the future.

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Section: Comfa and Comsia Modelsmentioning

confidence: 99%

Rational design of novel phenol ether derivatives as non-covalent proteasome inhibitors through 3D-QSAR, molecular docking and ADMET prediction

Yuan,

Ji,

Sun

et al. 2023

Explor Drug Sci

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“…The 3D-QSAR study was published using the a-ketotiazole arginine analogue inhibitors in 2011. 8 However, those basic groups were reported to have poor solubility and low bioavailability. Therefore, recent studies developed more promising compounds with nonbasic P1, the chloro-phenyl tetrazole group, as a novel anticoagulant oral drug.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Binding Mode for Human Coagulation Factor XI (FXI) Inhibitors

Cho¹,

Kim²,

Jung³

et al. 2013

Bulletin of the Korean Chemical Society

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The human coagulation factor XI (FXI) is a serine protease that plays a significant role in blocking of the blood coagulation cascade as an attractive antithrombotic target. Selective inhibition of FXIa (an activated form of factor XI) disrupts the intrinsic coagulation pathway without affecting the extrinsic pathway or other coagulation factors such as FXa, FIIa, FVIIa. Furthermore, targeting the FXIa might significantly reduce the bleeding side effects and improve the safety index. This paper reports on a docking-based three dimensional quantitative structure activity relationship (3D-QSAR) study of the potent FXIa inhibitors, the chloro-phenyl tetrazole scaffold series, using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Due to the characterization of FXIa binding site, we classified the alignment of the known FXIa inhibitors into two groups according to the docked pose: S1-S2-S4 and S1-S1'-S2'. Consequently, highly predictive 3D-QSAR models of our result will provide insight for designing new potent FXIa inhibitors.

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Exploring the selectivity of PI3Kα and mTOR inhibitors by 3D-QSAR, molecular dynamics simulations and MM/GBSA binding free energy decomposition

Hou

Luo

et al. 2013

Med. Chem. Commun.

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Comparative molecular field analysis and comparative molecular similarity indices analysis studies of α-ketothiazole arginine analogues inhibitors of coagulation factor XIa

Cited by 4 publications

References 18 publications

Rational design of novel phenol ether derivatives as non-covalent proteasome inhibitors through 3D-QSAR, molecular docking and ADMET prediction

Rational design of novel phenol ether derivatives as non-covalent proteasome inhibitors through 3D-QSAR, molecular docking and ADMET prediction

Characterization of Binding Mode for Human Coagulation Factor XI (FXI) Inhibitors

Exploring the selectivity of PI3Kα and mTOR inhibitors by 3D-QSAR, molecular dynamics simulations and MM/GBSA binding free energy decomposition

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