Experimentally Validated Novel Factor XIIa Inhibitors Identified by Docking and Quantum Chemical Post-processing

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Antithrombotic agents are crucial for managing thrombosis.
• Factor XIIa (FXIa) inhibitors represent a promising new class of antithrombotic drugs.
• Novel therapeutic strategies are needed to address thrombotic conditions.

Purpose of the Study:

• To identify and characterize novel classes of FXIa inhibitors.
• To explore chemical scaffolds for developing effective antithrombotic agents.
• To validate computational predictions through in vitro enzymatic assays.

Main Methods:

• Virtual screening of focused and large chemical libraries.
• Structure-based drug design utilizing SOL docking and MMFF94 force field.
• Postprocessing with PM7 semiempirical quantum-chemical method for binding enthalpy calculation.
• In vitro enzymatic assays to confirm inhibitory activity.

Main Results:

• Two novel classes of FXIa inhibitors were identified: triazolopyrimidine and spirocyclic furo[3,4-c]pyrrole derivatives.
• Virtual screening identified promising lead compounds based on docking scores and binding energy predictions.
• One compound from the large chemical library showed micromolar inhibitory activity against FXIa.
• Four triazolopyrimidine derivatives demonstrated FXIa inhibition at 30 μM concentration.

Conclusions:

• The identified triazolopyrimidine and spirocyclic furo[3,4-c]pyrrole derivatives are potential candidates for novel antithrombotic drugs.
• Computational methods, including virtual screening and quantum-chemical calculations, are effective in prioritizing compounds for FXIa inhibition.
• Further optimization of these novel inhibitor classes may lead to clinically viable antithrombotic therapies.