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A Molecular Dynamic Simulation, Structural Analysis, and Ex Vivo Insights into the P-glycoprotein-Mediated Interactions of Dietary Polyphenols with Cyclin-dependent Kinase Inhibitors: A Potential Strategy to Counteract Drug Efflux.
Patil, Prajakta Harish; Desai, Mrunal Pradeep; Anand, Vullendula Sai Krishna; Ray, Rajdeep; Shenoy, G Gautham; Dengale, Swapnil Jayant; Bhat, Krishnamurthy; Jagadish, P C.
Afiliación
  • Patil PH; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • Desai MP; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • Anand VSK; Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • Ray R; Research and Development, Maven Scientific Laboratories Private Ltd, Hyderabad,500046, Telangana, India.
  • Shenoy GG; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • Dengale SJ; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, 781101, India.
  • Bhat K; Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
  • Jagadish PC; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
Curr Med Chem ; 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-39279123
ABSTRACT

INTRODUCTION:

P-glycoprotein, an ATP-dependent efflux transporter, plays a crucial role in eliminating cellular toxins and affects the intracellular concentration and bioavailability of CDK 4/6 inhibitors. Moreover, dietary flavonoids are natural bio-enhancers that can effectively inhibit the efflux function of these transporters. Therefore, this study aimed to assess the impact of dietary polyphenols on the inhibition of P-glycoprotein and the subsequent efflux of CDK inhibitors palbociclib and ribociclib.

METHODS:

A molecular docking approach was implemented to evaluate the binding interaction characteristics of CDK4/6 inhibitors in the presence of dietary polyphenols at the ATP binding site. Furthermore, the stability of the complexes was evaluated in two conformations of P-glycoprotein, followed by an ex vivo everted gut sac experiment.

RESULTS:

The findings demonstrated that the binding of curcumin and quercetin with high affinity (-51.63 and 47.16 Kcal/mol) to ATP binding sites of P-glycoprotein-palbociclib and ribociclib inward conformation complexes resulted in good stability of complex and minimal fluctuation throughout the course of the simulation. It was evident from the everted gut sac ex vivo study that the presence of 100µM of curcumin resulted in an increase of 1.77 and 4.20-fold in the intestinal transit of palbociclib and ribociclib, respectively.

CONCLUSION:

The study emphasizes the significance of curcumin and quercetin as inhibitors of P-glycoprotein, demonstrating their potential to decrease the efflux of palbociclib and ribociclib, consequently contributing to their bioavailability enhancement.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Curr Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Emiratos Árabes Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Curr Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Emiratos Árabes Unidos