Computational Modeling of Photoswitchable Ligands for Optical Control of Intracellular Signaling Pathways

Abstract

Research into new treatments for neuropsychiatric disorders has progressed slowly over the past 50 years, with limited breakthroughs. However, the psychedelic renaissance is opening promising new avenues for therapy, offering the potential to reduce side effects and eliminate the need for chronic use of traditional antidepressants. A key goal in neuropharmacology today is to understand the role of altered states of consciousness in the antidepressant effects of these compounds. Achieving this requires novel pharmacological tools that can selectively activate specific neural populations while leaving others unaffected. Photopharmacology presents a compelling solution, leveraging external stimuli to reversibly control the activity of photoactive compounds with precision and minimal toxicity. In this thesis, we employ computational methods to explore the binding activity, membrane permeability, and photophysical properties of 5-HT2A receptor agonists. Using classical molecular dynamics, enhanced sampling techniques, quantum mechanics/molecular mechanics, and quantum mechanical approaches, we aim to deepen our understanding of these compounds and contribute to the development of innovative therapeutic strategies.