In silico development of adenosine A2B receptor antagonists for sickle cell disease

• Published in: Journal of biomolecular structure & dynamics 2022-01, Vol.40 (20), p.9592-9601
• Main Authors: da Silva, Anna Carolina Rocha, Araujo, Janay Stefany Carneiro, Pita, Samuel Silva da Rocha, Leite, Franco Henrique Andrade
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Antagonists - chemistry; Anemia, Sickle Cell - drug therapy; GPCR. Adenosine A2b receptor. Sickle cell disease. Homology modeling. Molecular dynamics; Humans; Hydrogen Bonding; Molecular Dynamics Simulation; Receptor, Adenosine A2B - chemistry
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2021.1934121

Sickle cell disease (SCD) is a disease resulting from mutation in the globin portion of hemoglobin caused by the replacement of adenine for thymine in the codon of the β globin gene. In Brazil, SCD affects about 0.3% of the black and Caucasian population. Until now, there is no specific treatment and the available drugs have several serious adverse effects which makes the search for new drugs an emergently need. The use of computational techniques can accelerate the drug development process by prioritization of molecules with affinity against essential targets. Adenosine A2b receptor (rA2b) has been studied in SCD due to its relationship with red blood cells concentration of 2,3-diphosphoglycerate which reduces the hemoglobin affinity for oxygen (O 2 ), facilitating its availability for the tissues. Then, development of rA2b antagonists could be helpful for the treatment of SCD. However, there is still no 3D structure of rA2b and to overcome this limitation, homology modeling should be applied. In this scenario, this study aims to build a suitable 3D model of rA2b by SWISS MODEL and to evaluate the structural aspects of rA2b with known antagonists that may be useful for the identification of new potential antagonists by molecular dynamics on a lipid bilayer environment using GROMACS 5.1.4. The complexes with antagonists ZINC223070016 and ZINC17974526 interacted with key residues by hydrophobic contacts and hydrogen bonds which stabilized them at the rA2b binding site. This intermolecular profile can contribute to the development of more potent rA2b antagonists. Communicated by Ramaswamy H. Sarma