ABSTRACT
Glioblastoma (GBM) is a highly malignant brain tumor characterized by a heterogeneous population of genetically unstable and highly infiltrative cells that are resistant to chemotherapy. Although substantial efforts have been invested in the field of anti-GBM drug discovery in the past decade, success has primarily been confined to the preclinical level, and clinical studies have often been hampered due to efficacy-, selectivity-, or physicochemical property-related issues. Thus, expansion of the list of molecular targets coupled with a pragmatic design of new small-molecule inhibitors with central nervous system (CNS)-penetrating ability is required to steer the wheels of anti-GBM drug discovery endeavors. This Perspective presents various aspects of drug discovery (challenges in GBM drug discovery and delivery, therapeutic targets, and agents under clinical investigation). The comprehensively covered sections include the recent medicinal chemistry campaigns embarked upon to validate the potential of numerous enzymes/proteins/receptors as therapeutic targets in GBM.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Glioblastoma , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Drug Discovery , Glioblastoma/drug therapy , Glioblastoma/pathology , HumansABSTRACT
BACKGROUND: Human serum albumin (HSA) is one of the most abundant proteins in the blood plasma, urine as well as in the organic matrix of renal calculi. Macromolecules present in the urine modulate kidney stone formation either by stimulating or inhibiting the crystallization process. OBJECTIVE: In the present study, the effect of HSA protein on the growth of calcium oxalate monohydrate crystal (COM) was investigated. METHODS: Crystal growth assay was used to measure oxalate depletion in the crystal seeded solution in the presence of HSA. HSA concentrations exhibiting effect on crystal growth were selected for FTIR and XRD analysis. In silico docking was performed on seven different binding sites of HSA. RESULTS: Albumin plays dual role in the growth of calcium oxalate crystallization. FTIR and XRD studies further revealed HSA exerted strain over crystal thus affecting its structure by interacting with amino acids of its pocket 1. Docking results indicate that out of 7 binding pocket in protein, calcium oxalate interacts with Arg-186 and Lys-190 amino acids of pocket 1. CONCLUSION: Our study confirms the role of HSA in calcium oxalate crystallization where acidic amino acids arginine and lysine bind to COM crystals, revealing molecular interaction of macromolecule and crystal in urolithiasis.
