Sakshi Patil* 1
Amisha Jamir Mulla 1
Tejashree Khamkar 2
About 85% of all instances of lung cancer worldwide are metastatic non-small cell lung cancer (NSCLC), the most prevalent and deadly kind of the disease.[1] Malignant epithelial cells that start in the lung and move to distant organs like the liver, brain, bone, and adrenal glands are what define it.[2] Due to the lack of early clinical symptoms, the majority of patients with non-small cell lung cancer (NSCLC) are discovered at an advanced or metastatic stage, making it a significant cause of cancer-related mortality.[3] High morbidity and mortality rates are still linked to NSCLC, underscoring the critical need for efficient targeted treatment approaches.[4] Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase involved in the control of cell proliferation, survival, and metastatic spread, is one of the most important molecular drivers in metastatic non-small cell lung cancer (NSCLC).[5] Chromosome rearrangements, most frequently the EML4–ALK fusion, are the primary cause of constitutive kinase activity and sustained oncogenic signaling in G1269A mutant ALK in NSCLC. [6] When G1269A mutant ALK is activated, downstream signaling pathways such PI3K/AKT, MAPK/ERK, and JAK/STAT are stimulated.[7] These pathways increase tumor growth, improve survival, enable invasion and metastasis, and provide resistance to apoptosis.[8]A specific subset of metastatic NSCLC patients have G1269A mutant ALK rearrangements, which are linked to aggressive disease biology and advanced-stage presentation.[9] However, the identification of the G1269A mutant ALK as a major oncogenic driver has made it a therapeutic target with clinical validation.[10] When compared to traditional chemotherapy, the development of G1269A mutant ALK-targeted tyrosine kinase inhibitors has significantly improved treatment outcomes in metastatic NSCLC, leading to longer progression-free survival, better central nervous system disease control, and an improved overall prognosis.[11] Computed tomography (CT) and positron emission tomography (PET), two modern imaging modalities, usually show large primary tumors with numerous metastatic lesions.[12] Metastatic NSCLC is still mostly incurable, and treatment is frequently palliative, despite advancements in surgery, chemotherapy, radiation, immunotherapy, and targeted medicines.[13] Tumor heterogeneity and genetic evolution often lead to the development of resistance to current treatments.[14] Therefore, the development of disease-modifying medications that target the molecular mechanisms behind tumor growth, metastasis, and therapy resistance is imperative.[15] The main purpose of the FDA-approved anticancer medication brigatinib, a next-generation tyrosine kinase inhibitor, is to prevent abnormal kinase signaling.[16] It has shown substantial anticancer efficacy in advanced lung malignancies and a strong binding affinity toward kinase domains.[17] Brigatinib was chosen as the lead chemical for structure-based drug discovery against G1269A mutant ALK in metastatic NSCLC because of its favorable pharmacokinetic profile and proven clinical safety.[18] We employed a virtual screening technique known as Morgan fingerprint to identify therapy candidates that function similarly to Brigatinib. [19] It is a computer method that examines the structure of molecules to identify hits based on their similarities. This work used CB-Dock, a program that predicts the location of the binding site based on the target's structure, to simulate and measure the mutation. Azelastine emerged from this strategy as a viable option for repurposing. [20] Second-generation histamine H1 receptor antagonists like azelastine are commonly used to treat allergic rhinitis and other allergic diseases. [21] It has a proven track record of clinical use and is well-characterized in terms of its pharmacokinetic profile, safety, and tolerability. [22] Emerging research indicates that azelastine has pleiotropic biological activity beyond its traditional function as an antihistamine, such as modulating inflammatory signaling and calcium homeostasis. [23] Azelastine may have anticancer-relevant effects, including suppression of migration and invasion, activation of apoptosis, and inhibition of tumor cell proliferation, according to recent preclinical research.[24] Interference with signaling pathways, particularly ALK-associated downstream pathways like PI3K/AKT and MAPK, as well as inflammation-driven mechanisms that lead to tumor growth and therapy resistance, is thought to be the cause of these effects.[25] Azelastine is a viable option for therapeutic repurposing in metastatic non-small cell lung cancer (NSCLC) due to its favorable safety profile, oral bioavailability, and ability to modify important signaling networks involved in tumor growth and metastasis.[26] Brigatinib and Azelastin's binding interactions with the protein were assessed in this work using a structure-based drug repurposing method.[27] This work attempts to investigate the viability of Azelastin as a potential alternative or complementary treatment drug targeting G1269A mutant ALK in metastatic NSCLC by comparing its docking performance with that of the well-known lead chemical brigatinib.[28] This study identifies Azelastine as a novel treatment option for metastatic non-small cell lung cancer using a Morgan fingerprint-guided, structure-based medication repurposing approach.[29] The method looks at novel ways to treat a condition that kills NSCLC patients by combining computer chemistry, virtual screening, and docking.[29]
MATERIALS AND METHODS
Ligand-Based Drug Repurposing
The DrugRep platform was used for ligand-based virtual screening. It has an experimental drug library with roughly 5,935 compounds and an FDA-approved medication library with roughly 2,315 compounds. These substances are obtained from DrugBank. [30-31] DrugRep can compare molecules using a variety of techniques, including five universal fingerprinting tools, LigMate, and FitDock.[32] Morgan fingerprints are quick and effective at identifying similar compounds, which is why we selected them.[33] Lead Compound A small-molecule tyrosine kinase inhibitor called brigatinib has been licensed to treat metastatic non-small cell lung cancer (mNSCLC), especially in tumours that have ALK rearrangements. [34] Because of its well-established kinase inhibitory profile, clinical effectiveness, and previous testing in resistant G1269A mutant ALK, brigatinib was chosen as the lead drug. [35] The Morgan Fingerprint Method. Using RDKit, the compounds' structures were transformed into 1,024-bit Morgan fingerprints with a radius of 2. [36] Next, the Tanimoto similarity scores between brigatinib and each of the 87 FDA-approved or investigational substances were calculated. [37] The list was reduced to roughly 20 compounds, which were then examined in greater detail, using a cutoff of ≥ 0.6. [38]
10.5281/zenodo.18411421