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Details of Grant 

EPSRC Reference: EP/X039420/1
Title: Conformations of musk odorants and their binding to human musk receptors
Principal Investigator: Sanz, Dr M
Other Investigators:
Fraternali, Professor F
Researcher Co-Investigators:
Project Partners:
Firmenich (Global)
Department: Chemistry
Organisation: Kings College London
Scheme: Standard Research
Starts: 01 May 2024 Ends: 30 April 2027 Value (£): 552,217
EPSRC Research Topic Classifications:
Analytical Science Tools for the biosciences
EPSRC Industrial Sector Classifications:
Related Grants:
Panel History:
Panel DatePanel NameOutcome
25 Oct 2023 EPSRC Physical Sciences Prioritisation Panel A October 2023 Announced
Summary on Grant Application Form
Structure and function are intimately linked in chemical and biological systems, and understanding their relationship underpins technological progress. Knowledge of the different conformations adopted by molecules is crucial to gain insight into their chemical and biological functions. However, despite its tremendous importance, conformational analysis remains an outstanding challenge for many processes. In this project we propose a novel approach to account for conformational flexibility and apply it to the long standing question of musk-olfactory receptor (OR) interactions.

Musk odorants are key compounds in perfumery due to their distinctive sensual notes and fixatives qualities. Natural musks are macrocycles with ketone and lactone functional groups. They have been used in perfumery since the beginning of the 20th century but they were very expensive due of the difficulties in their extraction and their complex synthesis. There were thus numerous attempts to develop new compounds with similar olfactory and fixative properties, which led to the appearance of other classes of musks. Many of these were found to be toxic and environmentally harmful, and are gradually being removed from use in consumer goods. Therefore designing and developing new biodegradable musks is still of huge industrial interest.

Progress on understanding the molecular features that determine musk-OR binding and musk smell has been hampered by the lack of structural data on macrocyclic musks and musk ORs. Conformational flexibility, an important characteristic of both odorants and ORs, is a major factor. Macrocyclic musks are expected to adopt many conformations, which has prevented their analysis by traditional spectroscopic techniques. ORs are also expected to be structurally flexible. Their importance has grown over the years, since they have been found in tissues outside the nose and have been proposed as drivers of cancer.

In this project we will address the challenge of advancing our understanding of musk smell by identifying macrocyclic musks' conformations for the first time, and determining their docking and binding trends on a refined model of a human musk OR. We will use a cutting-edge spectroscopic technique and multiscale computational methods. Our partnership with one of the leaders in the fragrance and flavor industry will allow us to investigate musks of industrial relevance and to get advantage of the industry's viewpoint on the application of structure-activity relationships. Our results will make a significant breakthrough in our knowledge of the molecular features and interactions mediating musk smell, and will pave the way to a rational design of environmentally safe musks.

The tools and results we will develop will be of further benefit to other areas of research including sustainable synthesis, perfumery, structural biology and molecular modelling.

Key Findings
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