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Docking studies on a refined human β2 adrenoceptor model yield theoretical affinity values in function with experimental values for R-ligands, but not for S-antagonists

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Abstract

G-protein coupled receptors (GPCR) belong to the largest group of membrane proteins involved in signal transduction. These receptors are implicated in diverse physiological and pathological events. The human β2 adrenergic receptor (hβ2AR) is one of the few GPCRs whose 3-D structures are available on the Protein Data Bank. Because there is great interest by drug developers for hβ2AR as a target, it is necessary to study its ligand-recognition process at the atomic level. The hβ2AR can recognize both R/S enantiomeric ligands, R-agonists result in a greater activation than do S-agonists (eutomers and distomers for activation, respectively), according to experimental results. In this work is reported the ligand recognition on a refined hβ2AR-structure of a set of well-known R/S-ligands by means of docking studies. Data obtained in silico were analyzed and compared with those reported in vitro. The theoretical affinity values were reproduced for agonists, but not for antagonist (or inverse agonists). However, theoretical data for R-antagonists are in function to experimental data. The theoretical results confirm the role of amino acids previously reported by mutagenesis studies due to their important roles in drug affinity and stereoselectivity.

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Acknowledgments

This work was supported by grants from Consejo Nacional de Ciencia Y Tecnología (CONACyT) (62488) and Comisión de Operación y Fomento de Actividades Académicas -Sección de Investigación y Posgrado del Instituto Politécnico Nacional (20080026). We would also like to thank Ian Ilizaliturri Flores for building and supporting the cluster used to run docking simulations.

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Authors and Affiliations

  1. Departamento de Fisiología y Farmacología, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, C.P. 11340, México, Mexico

    Marvin A. Soriano-Ursúa

  2. Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, C.P. 11340, México, Mexico

    Marvin A. Soriano-Ursúa & José G. Trujillo-Ferrara

  3. Laboratorio de Procesamiento Paralelo de la Sección de Estudios de Posgrado e Investigación, Centro de Innovación y Desarrollo Tecnológico en Cómputo (CIDETEC-IPN), Av. Juan de Dios Bátiz s/n casi esq. Miguel Othón de Mendizábal, Col. Nueva Industrial Vallejo, Delegación Gustavo A. Madero, C.P 07700, México, Mexico

    Jesús Álvarez-Cedillo

  4. Laboratorio de Modelado Molecular de la Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, C.P. 11340, México, Mexico

    José Correa-Basurto

Authors
  1. Marvin A. Soriano-Ursúa
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  2. José G. Trujillo-Ferrara
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  3. Jesús Álvarez-Cedillo
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  4. José Correa-Basurto
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Corresponding authors

Correspondence to Marvin A. Soriano-Ursúa or José Correa-Basurto.

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Soriano-Ursúa, M.A., Trujillo-Ferrara, J.G., Álvarez-Cedillo, J. et al. Docking studies on a refined human β2 adrenoceptor model yield theoretical affinity values in function with experimental values for R-ligands, but not for S-antagonists. J Mol Model 16, 401–409 (2010). https://doi.org/10.1007/s00894-009-0563-5

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  • DOI: https://doi.org/10.1007/s00894-009-0563-5

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