Molecular Docking of Pharmaceutical Cocrystal As a Ligand: Do We Need to Rethink?

Roy, Parag S.; Pandey, Noopur; Ghosh, Animesh

doi:10.1021/acs.cgd.2c01379

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…Autodock 4.0 software was employed for conducting docking calculations, aimed at optimizing the probable geometric crystal structure of the cocrystal [ 6 ]. Subsequently, molecular docking was performed to evaluate the binding of the cocrystal with the active site of the protein receptor, focusing on ligand-protein binding efficiency [ 28 ]. The protein receptor site EGFR crystal file (pdb ID: 1xkk, Uniport name: EGFR-Human) was downloaded from the protein data bank.…”

Section: Methodsmentioning

confidence: 99%

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Inam,

Yang,

et al. 2023

Pharmaceutics

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Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

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Section: Methodsmentioning

confidence: 99%

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Inam,

Yang,

et al. 2023

Pharmaceutics

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“…Similar concerns have been reported by Roy et al for molecular docking of pharmaceutical cocrystal. [41] They highlighted that based on the dissociation/solution-mediated phase transformation of cocrystals, molecular docking studies using a cocrystal as a ligand in the active site of a receptor is a complicated affair to estimate its biological efficacy. However, some researchers have hypothesized cocrystals can retain transient in solution and change the interaction with receptors to modify the biological properties.…”

Section: Anticancermentioning

confidence: 99%

Cocrystallization for Improving Anticancer Activity of Drugs

Alvani,

Shayanfar

2024

Cryst. Res. Technol.

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Cocrystallization can change the physicochemical and pharmacokinetic properties of active pharmaceutical ingredients (API) and improve biological activities. This study focuses on the documented biological activities of APIs in cocrystal form, specifically those with anticancer properties. Additionally, the mechanisms by which these APIs exhibit modified anticancer effects are discussed. Generally, this technique can change anticancer activity through solubilization, enhancing dissolution rate, permeability improvement, stabilization, producing a slow‐release form, and retaining transient in solution and interaction with receptors.

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“…). − It is a form of condensation of multicomponent substances in the solid state. Drug cocrystals are specifically defined as containing one or more active pharmaceutical ingredients (API), and both the API and the cocrystal former (CCF) are solid at room temperature, where the CCF must be a biologically acceptable small molecule former . Generally, drug cocrystals can be prepared by various methods, such as solution crystallization, comilling, , suspension crystallization, and hot melt extrusion .…”

Section: Introductionmentioning

confidence: 99%

“…Drug cocrystals 4 are specifically defined as containing one or more active pharmaceutical ingredients (API), and both the API and the cocrystal former (CCF) are solid at room temperature, where the CCF must be a biologically acceptable small molecule former. 5 Generally, drug cocrystals can be prepared by various methods, such as solution crystallization, 6 comilling, 7,8 suspension crystallization, 9 and hot melt extrusion. 10 Drug cocrystals can significantly improve the dissolution behavior, dissolution rate, and stability of drugs, and the study of drug cocrystals can help to improve the physicochemical properties of drugs and promote the entry of insoluble drugs into clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Determination of the Asymmetric Ternary Phase Diagram and Preparation of Theophylline–Isonicotinamide Cocrystals

Liu,

Yang,

Wang

et al. 2024

Crystal Growth & Design

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The solid−liquid phase equilibrium data of theophylline and isonicotinamide in selected solvents (isopropanol, N,Ndimethylformamide, and n-pentanol) were determined by using the static method at 298.15 and 308.15 K under 101.325 kPa. The ternary phase diagram was plotted, and it was concluded that it is an asymmetric phase diagram. The mechanism of solid-phase formation of cocrystals during the determination of the ternary phase diagram is discussed. Excessive amounts of THE and INA cause the system to become supersaturated. As the cocrystal forms, the solubility of THE and INA decreases. When the system is on the solvation curve of the cocrystal, the activity coefficients of THE and INA drop to critical values and cocrystal formation stops. Based on the analysis of phase solubility diagrams for cocrystals, two routes for obtaining the cocrystal of THE-INA from solution have been proposed and validated. For route 1, concentrations of THE and INA in the solution are adjusted to the appropriate concentrations, and then, solvent evaporation is performed to achieve crystallization. For route 2, an amount of THE was added to a highly concentrated INA solution. The variation of the main constitutive forces of cocrystal formation is explored by molecular simulation simulations. The types of interaction forces and their interaction energies in ternary systems are identified. In addition, the melting temperature and enthalpy of fusion of the THE-INA cocrystal obtained during ternary phase diagram determination were determined to be 462.26 K (onset) and 131.69 J/g, respectively.

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Molecular Docking of Pharmaceutical Cocrystal As a Ligand: Do We Need to Rethink?

Cited by 4 publications

References 17 publications

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Cocrystallization for Improving Anticancer Activity of Drugs

Determination of the Asymmetric Ternary Phase Diagram and Preparation of Theophylline–Isonicotinamide Cocrystals

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