Protein flexibility in docking and virtual screening on the beta 2 adrenergic receptor

ZAMBRANA MONTAÑO, ROMINA; CAVASOTTO, CLAUDIO NORBERTO

Ciudad Autónoma de Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

Facultad de Farmacia y Bioquímica - Universidad de Buenos Aires

ABSTRACT: Recently, insecticides that disrupt G protein-coupled receptor (GPCR) targets in the arthropod vectors (that transmited infectious diseases, such as dengue, yellow fever, Zika and leishmaniasis) have been proposed against resistant pest populatons [1]. In the past, in silico methods have been successful to identify drug leads using docking-based virtual screening [2].However, these methods generally do not consider the flexibility of the protein, decreasing the effectiveness of finding new drugs.In this work, we focused on the β2 Adrenergic Receptor (β2AR), which is involved in the treatment of multiple human diseases [3-5]. The aims of this study are to analyze how the lack of flexibility for the agonist and antagonist/inverse-agonist modes of β2AR structures impacts on molecular docking. On the other hand, we study the impact of flexibility on enrichment in virtual screening for the same receptor using the rigid receptor docking approach and theReceptor Ensemble Docking method [6].References:[1] McCusker, E. C., Bane, S. E., O?Malley, M. A., y Robinson, A. S. (2007). Heterologous GPCR expression: A bottleneck to obtaining crystal structures. Biotechnology Progress, 23, 540?547.[2] Spyrakis, F., Cavasotto, C. N. (2015). Open challenges in structure-based virtual screening: Receptor modelling, target flexibility consideration and active site water molecules description. Archives of Biochemistry and Biophysics, 583, 105-19.[3] Charlotte, K. B. & Raymond, B. P. (2003). Signaling and regulation of G protein- coupled Receptors in airway smooth muscle. Respiratory Research, 4, 2-23.[4] Johnson, M. (2006). Molecular mechanism of β2-adrenergic receptor function, response an regulation. Journal of Allergy and Clinical Immunology, 117, 18-24.[5] Yanxiang, N., Xiaohui, Z., Guobin, B., Lin, Z., Lin, T., Zhu, W., Min, S., Jiaxiang, X., Yun, B., Gang, P. (2006). Activation of β2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nature Medicine, 12, 1390-1396.[6] Cavasotto, C. N., Abagyan, R. A. (2004). Protein flexibility in ligand docking and virtual screening to protein kinases. Journal of Molecular Biology, 337, 209-225.