ABSTRACT
Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 µM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 µg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.
Subject(s)
Antitubercular Agents/chemistry , Drug Design , Folic Acid Antagonists/chemistry , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Folic Acid Antagonists/chemical synthesis , Folic Acid Antagonists/pharmacology , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium tuberculosis/enzymology , Nitrogen/chemistry , Tetrahydrofolate Dehydrogenase/metabolismABSTRACT
AIMS AND OBJECTIVES: The aim of this study was to retrospectively correlate FDG uptake in primary Ewing sarcoma family of tumors (ESFT) with tumor behavior, and to evaluate whether FDG PET can be used to predict response to neoadjuvant chemotherapy (NACT) in this patient group. METHODS: Out of the total 54 patients of recently diagnosed ESFT who underwent pretreatment FDG PET imaging, group I included patients without metastasis at presentation (n = 34) and group II included those with metastasis at presentation (n = 20). Fourteen of these patients had undergone FDG PET after 4 cycles of induction chemotherapy and surgical resection of primary tumor. In this subgroup of 14 patients, maximum standardized uptake value (SUVmax) of primary tumor was estimated before and after 4 cycles of induction chemotherapy and was correlated with the histopathological response in terms of necrosis in the tumor specimen. RESULTS: Mean SUVmax in the primary tumor in group I patients was 6.84 and in group II patients, it was 11.31. The difference between mean SUVmax of these 2 groups was significant by Wilcoxon test analysis, with P < 0.01. In group II patients, SUVmax in metastasis with maximum FDG uptake was consistently lower as compared with that of primary tumor. In subgroup of 14 patients, Pearson correlation analysis showed that percentage change in SUVmax of primary tumor correlated well with percentage necrosis on histopathological examination (P < 0.01). CONCLUSION: FDG uptake in primary ESFT reflected its metastatic potential and hence the aggressive behavior. The significant correlation between change in metabolic activity of the primary tumor and histopathological response after neoadjuvant chemotherapy suggests that FDG PET may be an ideal noninvasive method to assess tumor behavior and response to therapy in ESFT.
