ABSTRACT
Acute Myeloid Leukaemia (AML) is a blood cancer, which affects the red blood cells in the bone marrow. Of the possible proteins that are affected in AML, fms-like tyrosine kinase 3 (FLT3) has long been recognized as a potential therapeutic target as it affects the other signaling pathways and leads to a cascade of events. First-generation inhibitors sorafenib and midostaurin, as well as secondgeneration agents such as quizartinib and crenolanib are known. It is of interest to identify new compounds against FLT3 with improved activity using molecular docking and virtual screening. Molecular docking of existing inhibitors selected a top scoring bestestablished candidate Quizartinib having PubChem CID: 24889392. Similarity searching resulted in compound XGIQBUNWFCCMASUHFFFAOYSA-NPubChemCID: 44598530 which shows higher affinity scores. A comparative study of both the compounds using a drug-drug comparison, ADMET studies, boiled egg plot and pharmacophore parameters and properties confirmed the result and predicted the ligand to be an efficient inhibitor of FLT3.
ABSTRACT
BACKGROUND: According to DCEG investigation, the compared results of the osteosarcoma incidences in different continents, reported it to be the most diagnosed in adolescents and adults above 60 yrs. old. Less than 15% of patients get cured with surgery alone but the addition of chemotherapy to the treatment increases the survival rate of patient by 58%-76%. Surgical resection and aggressive chemotherapy protocols are effective to an extent but have failed to improve the 5-year overall survival rate. Indubitably, new drugs and new therapeutic targets are required to improve the outcome as well as to diminish the long-term toxicities associated with the current benchmark of treatment. STAT3 appears to be an important mediator of chemoresistance in osteosarcoma. RESULTS: Experimental evidence clearly demonstrate the disruption of STAT3 signaling which inhibits the survival and proliferation of osteosarcoma and decreases the growth of disease. This prevailing study approach is by molecular docking, virtual screening to elucidate inhibitor with superior affinity against STAT3 to have a cautious pharma profile. To rectify the best-established drug with high affinity, Mol dock algorithm is executed. The compound Sorafenib (Pub CID 216239) having high-affinity scores is subjected to another similarity search to retrieve the drugs with similar properties. The virtual screened compound with PubChem CID-44815014 as per BOILED-Egg plot reveals its high affinity. CONCLUSION: Comparative study and ADMET study both showed the compounds to have equivalent properties, whereas interestingly the virtual screened compound having PubChem CID-44815014 is seen to have the lowest rerank score. These drugs are identified to have high potential to act as STAT3 inhibitors and probably can be considered for further studies in wet lab analysis.
