Docking, MD Simulations, and DFT Calculations: Assessing W254's Function and Sartan Binding in Furin

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Furins are serine endoproteases crucial for metabolism and pathogen activation, making them therapeutic targets.
• Dichlorophenyl-pyridine (BOS) compounds inhibit furin via an induced-fit mechanism involving tryptophan W254.
• Sartans are AT1 antagonists that inhibit angiotensin II effects.

Purpose of the Study:

• To computationally investigate the binding mechanism of BOS compounds with human furin.
• To evaluate the potential of sartans as furin inhibitors and their interaction with BOS ligands.

Main Methods:

• Density Functional Theory (DFT) and ONIOM multiscaling methodologies were used to study BOS compound binding.
• Molecular docking and molecular dynamics simulations were employed to assess sartan binding and interactions.

Main Results:

• Calculated binding enthalpies for W254 with furin-BOS were -32.8 kcal/mol (open) and -18.8 kcal/mol (closed).
• A significantly reduced torsion barrier (30 kcal/mol) for W254 was observed due to environmental relaxation.
• Sartans consistently bound within the furin cavity, indicating potential inhibitory activity and competitive binding with W254.

Conclusions:

• Computational methods provide insights into furin inhibition mechanisms by BOS compounds.
• Sartans demonstrate potential as furin inhibitors, interacting with the same residues as W254.
• Sartan binding may lead to competitive inhibition, impacting their pharmacological efficacy and drug interactions.