Halogen Bonding Hot Spots as a Constraint in Virtual Screening: A Case Study of 5-HT₇R

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Serotonin 7 receptors (5-HT7R) are targets for neurological disorders.
• Halogen bonding (XB) is an important non-covalent interaction in drug design.
• Identifying specific amino acid residues (XB hot spots) can guide ligand design.

Purpose of the Study:

• To apply a molecular modeling approach to identify privileged amino acids for halogen bonding in 5-HT7R.
• To utilize identified XB hot spots in a virtual screening protocol to discover novel ligands.
• To validate the predictive accuracy of the virtual screening method.

Main Methods:

• Employed a molecular modeling approach to identify XB hot spots within the 5-HT7R structure.
• Utilized the identified S5x42 residue as a constraint in a virtual screening protocol.
• Screened over 8 million commercially available compounds, selecting 156 for in vitro testing.
• Performed in vitro assays to determine binding affinity for 5-HT7R.

Main Results:

• The virtual screening protocol identified 63 XSAR sets with potential 5-HT7R activity.
• Achieved 68% accuracy in predicting halogenated derivatives with enhanced binding affinity.
• Discovered a halogen bond between S5x42 and a chlorine atom, increasing binding affinity by 35.4-fold.
• Molecular dynamics simulations revealed the formation of a bifurcated halogen bond with S5x42.

Conclusions:

• The molecular modeling approach effectively identifies privileged amino acids for halogen bonding in 5-HT7R.
• Virtual screening using XB hot spots is a viable strategy for discovering potent ligands.
• Halogen bonding, particularly with S5x42, significantly enhances ligand binding affinity to 5-HT7R.