# Computational Analysis of Lenalidomide and Pomalidomide Enantiomers’ Binding Interactions With Prostaglandin (PG)-Protein: Implications for Inflammatory Activity in Cancer

## TL;DR

This study explores how different forms of two cancer drugs interact with a protein linked to inflammation in tumors, suggesting a new way to fight cancer.

## Contribution

The study reveals distinct binding affinities of drug enantiomers to a prostaglandin protein, offering new insights into their anti-inflammatory mechanisms in cancer.

## Key findings

- Both enantiomers of Lenalidomide and Pomalidomide bind strongly to Pg-protein with notable differences in binding energy.
- Hydrogen bonds formed between drug enantiomers and key amino acid residues suggest a consistent binding mode.
- The drugs may target the Pg-protein pathway to influence inflammatory activity in cancer progression.

## Abstract

Background: Lenalidomide and Pomalidomide are chiral immunomodulatory drugs (IMiDs) and have antiangiogenic and anti-immunomodulatory activity. Each enantiomer may have distinct binding and biological activity. This study aimed to explore the in-silico binding of both enantiomers of Lenalidomide and Pomalidomide with Prostaglandin and its potential impact on persisting inflammatory activity in cancer. This can further provide insight into the transport of pro-inflammatory mediators and their potential implications for the inflammatory microenvironment within tumors.

Materials and methods: Molecular docking studies were performed to explore the binding potential of both enantiomers of Lenalidomide and Pomalidomide with Pg protein. The crystal structure of Pg-protein (PDB ID: 1IW7) was obtained from the Protein Data Bank.

Results: The binding energies for (-)-Lenalidomide and (+)-Lenalidomide were -6.7 and -7.2 kcal/mol, respectively, while the binding energies for (-)-Pomalidomide and (+)-Pomalidomide were -7.8 and -8.1 kcal/mol, respectively. The binding mode analysis revealed that all four compounds formed hydrogen bonds with key amino acid residues of Pg-protein. The hydrogen bond distances for (-)-Lenalidomide, (+)-Lenalidomide, (-)-Pomalidomide, and (+)-Pomalidomide were 2.1 Å, 2.0 Å, 2.2 Å, and 2.1 Å, respectively.

Conclusions: The present study suggests that both enantiomers of Lenalidomide and Pomalidomide have a high affinity for Pg-protein and can effectively target the Pg-protein pathway to persist inflammatory activity in cancer. By targeting inflammation-mediated processes, these drugs may offer a novel strategy to combat tumor progression.