Identification of non-resistant ROS-1 inhibitors using structure based pharmacophore analysis.
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.
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Disha
D
Pathak
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Navriti
N
Chadha
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India. Electronic address: omsilakari@gmail.com.
Om
O
Silakari
D000631:Aminopyridines; D000077547:Crizotinib; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D008024:Ligands; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib
Lung cancer; Molecular docking; Molecular dynamics; ROS-1; Receptor-ligand pharmacophore