Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• The bile salt export pump (BSEP) is crucial for bile acid transport from hepatocytes.
• BSEP inhibition can cause drug-induced cholestasis and liver injury.
• In silico methods are needed for early identification of BSEP inhibitors in drug discovery.

Purpose of the Study:

• To develop a homology model of BSEP for structure-based virtual screening.
• To classify compounds as BSEP inhibitors or non-inhibitors using docking.
• To identify key interactions between ligands and BSEP.

Main Methods:

• Homology modeling of BSEP using a mouse P-glycoprotein structure (PDB ID: 4M1M).
• Docking-based classification of 1212 compounds using the ChemScore function.
• Assessment of model applicability domain and analysis of protein-ligand interactions.

Main Results:

• Achieved 81% prediction accuracy on the training set and 73% on external test sets.
• Identified key functional group-amino acid residue interactions for ligand binding.
• Structure-assisted models provided insights into putative protein-ligand interactions.

Conclusions:

• Homology modeling and docking offer a viable structure-assisted approach for identifying BSEP inhibitors.
• This method complements faster ligand-based approaches by providing interaction details.
• The developed models can aid in flagging potential BSEP inhibitors early in drug development.