Homology modeling and molecular docking studies of Drosophila and Aedes sex peptide receptors

• The 3D structures of drosophila and aedes sex peptide receptors were generated by using the GEnSeMBLE method.
• To investigate the binding mechanism of the new small molecule agonists, molecular docking studies were performed.
• The Ser3.25, Tyr5.35 and Phe2.67 residues of DrmSPR would be important for binding of small molecule agonist compound 1.
• Molecular docking studies supported the previously observed structure-activity relationships of the reference compounds.
• The structural differences between DrmSPR and AedesSPR lead to the species selectivity of compound 1.

The Drosophila melanogaster sex peptide receptor (DrmSPR), which is a G protein-coupled receptor (GPCR), is known as the specific receptor for sex peptide (SP). It is responsible for the reproductive behavior in the Drosophila model system; in particular, it is involved in the post-mating responses such as the increase in egg-laying ability and decrease in receptivity in females. In a previous study, we discovered a small molecule agonist of DrmSPR for the first time, which could not, however, activate Aedes aegypti SPR (AedesSPR). To investigate the binding mechanism of the small molecule agonist of DrmSPR, the ensemble structures of low-lying packing structures of DrmSPR and AedesSPR were assembled using the GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) method. The generated homology models exhibited the typical pattern of inter-helical interactions of the class A GPCRs. The docking experiments of the small molecule agonist suggest that Tyr5.35 and Phe2.67 residues may be involved in a hydrophobic interaction and that Ser3.25 forms a hydrogen bond with the agonist. Additionally, we found that the docking results were consistent with the experimental data of the reference compounds with variable agonistic activities. Moreover, a potential distinction of the putative binding sites in two GPCR models of DrmSPR and AedesSPR, which was determined in this study, can explain the selective action of the agonist for DrmSPR but not for AedesSPR.

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