FLT3 inhibitor design using molecular docking based virtual screening for acute myeloid leukemia.

Padmini Gokhale,Aashish Pratap Singh Chauhan,Anushka Arora,Sanjeev Kumar Singh,Anuraj Nayarisseri,Natasha Khandekar

doi:10.6026/97320630015104

Padmini Gokhale, Aashish Pratap Singh Chauhan + Show 4 more

Open Access

https://doi.org/10.6026/97320630015104

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Journal: Bioinformation	Publication Date: Feb 28, 2019
Citations: 26	License type: cc-by

Affiliation: Alagappa University

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.

Highlights

The incidence frequency of acute myeloid leukemia (AML) increases with age, from 1.3 per 100,000 in a population of patients who are less than 65 years old
Considering the current treatments, as much as 70% of patients are 65 years or older and have lower survival rates, which are mostly confirmed from 1 year after diagnosis
An increase to about 21,450 new cases of acute myeloid leukemia (AML) mostly in adults and 10,920 deaths from AML again almost all are adults are obtained from the population consensus

Summary

Background

The incidence frequency of AML increases with age, from 1.3 per 100,000 in a population of patients who are less than 65 years old. An increase to about 21,450 new cases of acute myeloid leukemia (AML) mostly in adults and 10,920 deaths from AML again almost all are adults are obtained from the population consensus. Acute Myeloid Leukemia has 6 major classifications namely, AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, myeloid sarcoma, myeloid proliferations related to Down syndrome and AML not otherwise specified. LLC, New York, NY) where, these were optimized through OPLS 2005 force field algorithm [38,39,40,41,42] Both the structure files of the protein and the ligands were saved for the ease of processing for docking analysis. Placing of Simplex Evolution at max steps 300 and neighbor distance faster 1.00 This confirms that the predominant molecule obtained after docking forms a stable complex.

Results and Discussion

Non-required

Conclusion