Structure modelling of odorant receptor from Aedes aegypti and identification of potential repellent molecules

Comput Struct Biotechnol J. 2023 Mar 6:21:2204-2214. doi: 10.1016/j.csbj.2023.03.005. eCollection 2023.

Abstract

Odorant receptors (ORs) are important class of proteins involved in olfactory behaviour of insects. These are GPCR-like heptahelical transmembrane proteins with inverted topology compared to GPCR and require a co-receptor (ORco) for their function. OR function can be modulated through small molecules and negative modulation can be beneficial in case of disease vectors like Aedes aegypti. OR4 of A. aegypti is implicated in host recognition through human odour. Aedes aegypti is a vector for viruses that spread diseases like dengue, Zika and Chikungunya. In this study, we have attempted to model the full-length structure of OR4 and the ORco of A. aegypti due to lack of experimental structure. Further, we have screened a library of natural compounds (>0.3 million) along with known repellent molecules against ORco and OR4. Many natural compounds, including those from plants like Ocimum tenuiflorum (Holy Basil) and Piper nigrum (Black pepper), were found to have better binding affinity towards ORco compared to known repellents like DEET providing an alternative to existing repellent molecules. For specific inhibitor of OR4, several natural compounds (including those from plant like Mulberry) were identified. Further, we have utilized multiple docking approaches and conservation analysis to understand the interaction between OR4 and ORco. It was observed that the residues from the seventh transmembrane helix of OR4 and pore forming helix of ORco could play an important role along with known intracellular loop 3 residues in mediating the heteromer formation of OR and ORco.

Keywords: Aedes aegypti; Molecular dynamics simulation; OR4; Odorant receptor; Structure modelling; Virtual screening.