Robust fragment-based method of calculating hydrogen atom transfer activation barrier in complex molecules

Area of Science:

• Computational chemistry
• Chemical kinetics
• Drug discovery

Background:

• Non-covalent interactions (NCI) influence reaction rates, particularly for reactions with low activation barriers at low temperatures.
• Hydrogen-atom-transfer (HAT) reactions are relevant to the oxidative stress of active pharmaceutical ingredients (APIs).
• Complex APIs exhibit conformational flexibility, affecting reaction dynamics.

Purpose of the Study:

• To develop an automated workflow for generating HAT transition-state (TS) geometries for flexible APIs.
• To evaluate the influence of NCIs on free activation energies using multi-conformational transition-state theory (MC-TST).
• To investigate the impact of conformational complexity and multiple activation pathways on reaction rates.

Main Methods:

• Automated generation of HAT transition-state (TS) geometries.
• Application of multi-conformational transition-state theory (MC-TST).
• Analysis of non-covalent interactions (NCI) and conformational effects on activation energies.
• Fragment-based method for calculating overall activation barriers.

Main Results:

• NCIs and conformational exchange significantly affect activation energies for complex APIs.
• Multiple activation pathways and conformational flexibility must be considered in calculations.
• Structural elements and NCIs outside the reaction site have minimal impact on the TS core and covalent barrier.
• NCIs strongly influence reactant binding, affecting the overall activation barrier.

Conclusions:

• Conformational dynamics and non-covalent interactions are critical for understanding reaction mechanisms in APIs.
• An automated workflow and MC-TST provide valuable insights into activation processes.
• A fragment-based approach offers an economical method for predicting overall activation barriers.