Thermal Half-Lives of Azobenzene Derivatives: Virtual Screening Based on Intersystem Crossing Using a Machine Learning Potential

Abstract

Molecular photoswitches are the foundation of light-activated drugs. A key photoswitch is azobenzene, which exhibits trans−cis isomerism in response to light. The thermal halflife of the cis isomer is of crucial importance, since it controls the duration of the light-induced biological effect. Here we introduce a computational tool for predicting the thermal half-lives of azobenzene derivatives. Our automated approach uses a fast and accurate machine learning potential trained on quantum chemistry data. Building on well-established earlier evidence, we argue that thermal isomerization proceeds through rotation mediated by intersystem crossing, and incorporate this mechanism into our automated workflow. We use our approach to predict the thermal half-lives of 19,000 azobenzene derivatives. We explore trends and trade-offs between barriers and absorption wavelengths, and open-source our data and software to accelerate research in photopharmacology.

On the Simulation of Thermal Isomerization of Molecular Photoswitches in Biological Systems

“…Axelrod et al recently employed this method to train machine learning models for quickly predicting thermal half-lives of AB derivatives in solution. In that study, both the S 0 → T 1 → S 0 pathway and implicit solvation effects were taken into account when constructing the training dataset …”

“…The nonadiabatic transition-state theory (NA-TST) ,, was employed to describe the reaction rate ( k NA‑TST ) and quantify the timescale ( t NA‑TST ) of the events at ISC geometry for the PST family in the gas phase using eq k normalN normalA ‐ normalT normalS normalT = k normalI normalS normalC · e − β normalΔ E where Δ E is the energy difference between the cis -PST minima on the S 0 state and the highest crossing point between the S 0 and T 1 states. k ISC is the intersystem crossing rate calculated using eq ,, k I S C = π 3 / 2 α 2 h λ / false( k normalB T false) · true[ 1 + 1 2 .25em · exp ( 1 12 α 2 ( k B T λ ) 3 ) true] …”

“…Second, the isomerization of AB-based molecular photoswitches occurs through competing pathways involving intersystem crossing, bending angle inversion, or hydrazone tautomer. Ground-state isomerization from cis -to- trans isomer may involve two intersystem crossing events (S 0 to T 1 , followed by T 1 to S 0 ), which could lower the energy barrier compared to pathways involving only the S 0 state. , Bending the C–NN angle to nearly 180° is an alternative mechanism to the central torsion rotation. The hydrazone tautomer mechanism suggests that the transient protonation of the NN bond lowers the bond order and hence the isomerization barrier.…”

“…Popular single-reference methods like density functional theory (DFT), although computationally inexpensive and commonly used, 5−8 cannot accurately describe transition-state structures and isomerization pathways. 9 Second, the isomerization of AB-based molecular photoswitches occurs through competing pathways involving intersystem crossing, bending angle inversion, or hydrazone tautomer. Ground-state isomerization from cis-to-trans isomer may involve two intersystem crossing events (S 0 to T 1 , followed by T 1 to S 0 ), which could lower the energy barrier compared to pathways involving only the S 0 state.…”

Azobenzene-Functionalized UiO-66-NH2: Solid Base Catalysts with Photocontrollable Activity

“…The azobenzene group of PAC contains a π-conjugated system; when irradiated with UV and visible light, the azobenzene groups of PAC and UNP- x can undergo a cis / trans isomerization process, and there are many mechanism explanations for photoisomerization of the azobenzene group (rotation, inversion, concerted inversion, inversion-assisted rotation, etc. ). , In a rotational process, the NN π-bond breaks, allowing for free rotation around the N–N bond, and the C–NN–C dihedral angle changes, while the NN–C angles remain fixed at ∼120°; then a configuration transition was achieved. The photoresponsive behavior of PAC was first characterized by a UV–vis spectrometer.…”