Related Experiment Video
Updated: Mar 14, 2026
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Identification of non-resistant ROS-1 inhibitors using structure based pharmacophore analysis
Disha Pathak1, Navriti Chadha1, Om Silakari1
1Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Abstract:
Proto-oncogene receptor tyrosine kinase ROS-1 plays a key role in regulating a variety of cancers mainly non-small cell lung cancer (NSCLC). The marketed ROS-1 inhibitors such as Crizotinib suffer from the tribulations of growing resistance due to mutations primarily Gly2032Arg in the ROS-1 protein. To curb the problem of resistance, researchers have developed inhibitors such as Lorlatinib against the mutant protein. The present study was designed to identify inhibitors against wild type (WT) as well as mutant ROS-1 protein that will offer a broader spectrum of activity. Exploring crystal structure of ROS-1 complexed with Lorlatinib, receptor-ligand pharmacophore model was developed using Discovery Studio (DS) software. The developed pharmacophore model consisted of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and two hydrophobic features (HY), subsequently utilized for virtual screening of commercially available databases and the retrieved hits were further subjected to fitness score and Lipinski's filter. Thereafter, the retrieved hits were docked in WT and mutated (Gly2032Arg) proteins of ROS-1. Total five molecules were retrieved with good docking scores and good binding interactions within the active site of WT and mutated ROS-1. The binding energies of the ligand-receptor complexes were predicted via calculation of MM-GBSA score. To predict the stability of the ligand receptor complexes with mutant and wild type proteins, molecular dynamic simulation was performed. Thus, these identified hits show good binding affinities with WT and mutant ROS-1 proteins that may be further evaluated for their in-vitro/in-vivo activity.
Insights
Researchers identified novel inhibitors targeting both wild-type and resistant mutant ROS1 proteins, crucial in non-small cell lung cancer (NSCLC). These compounds show promising binding affinities for potential therapeutic development against ROS1-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Proto-oncogene receptor tyrosine kinase ROS1 is implicated in various cancers, notably non-small cell lung cancer (NSCLC).
- Acquired resistance to existing ROS1 inhibitors (e.g., Crizotinib) often arises from specific mutations, such as Gly2032Arg.
- Targeting both wild-type and resistant ROS1 mutations is crucial for developing more effective cancer therapies.
Purpose of the Study:
- To identify novel small molecules with broad-spectrum activity against both wild-type (WT) and mutant ROS1 proteins.
- To develop a pharmacophore model based on the ROS1-Lorlatinib complex for virtual screening.
- To evaluate the binding affinity and stability of potential inhibitors against WT and Gly2032Arg mutant ROS1.
Main Methods:
- Development of a receptor-ligand pharmacophore model using Discovery Studio based on the ROS1-Lorlatinib crystal structure.
- Virtual screening of commercial databases using the developed pharmacophore model.
- Inclusion of fitness score and Lipinski's filter for hit selection.
- Molecular docking of retrieved hits into WT and Gly2032Arg mutant ROS1 active sites.
- Binding energy prediction using MM-GBSA and molecular dynamic simulations for stability assessment.
Main Results:
- A pharmacophore model comprising hydrogen bond acceptor, hydrogen bond donor, and two hydrophobic features was generated.
- Virtual screening yielded five potential inhibitor molecules with favorable docking scores and binding interactions.
- These molecules exhibited good binding affinities to both WT and Gly2032Arg mutant ROS1.
- Molecular dynamics simulations indicated stable interactions between the identified ligands and ROS1 proteins.
Conclusions:
- The study successfully identified five novel compounds with significant binding affinity for both wild-type and resistant mutant ROS1 proteins.
- These compounds represent promising candidates for further preclinical evaluation (in vitro/in vivo) as potential therapeutics for ROS1-driven cancers.
- The developed pharmacophore model serves as a valuable tool for future drug discovery efforts targeting ROS1.
More Related Videos
08:31Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
10:29Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
