INTERNATIONAL CONGRESS OF
PharmacoGenetics
Exploring Cytarabine’s Affinity for SMO receptor in Hedgehog pathway in AML via Molecular Docking
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Melika Naderi,1,*
1. Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Introduction: Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow, leading to an overproduction of abnormal white blood cells. The Hedgehog signaling pathway is pivotal for normal cell proliferation and development. Still, when it becomes dysregulated, it can lead to the unbridled growth of cancer cells. The Smoothened (SMO) receptor is a key component of this pathway, and its activation is related to the progression of leukemia. One of the most constantly employed treatments for leukemia is Cytarabine, a chemotherapeutic agent that effectively disrupts DNA synthesis. This interference serves to target cancer cells, eventually leading to their destruction. The impact of Cytarabine on the hedgehog pathway remains to be determined. Nonetheless there are promising indications of its potential as an adjunct therapy to hedgehog pathway inhibitors. The ideal of this study is to estimate the affinity of Cytarabine to SMO protein and to hypothecate the probable association of Cytarabine through the hedgehog pathway in leukemia.
- Methods: In this research, initially, the SMO protein structure was obtained from the Uniprot website, then necessary preparations, such as adding charge and hydrogen ions, were done using Chimera software. The three-dimensional structure of the Cytarabine was downloaded from the PubChem website. The binding site of the SMO protein was determined using Deepsite. [Center; X: -13.926, Y: -29.800, Z: -12.1197 and Dimensions (Angstrom); X, Y, Z: 25.00] Finally, the molecular docking process was conducted using AutoDock Vina in PyRx 0.8 to test the binding status of Cytarabine to SMO protein.
- Results: Following the completion of the docking process of Cytarabine with SMO protein, using PyRx software, the obtained results are as followed. For each model, the data belongs to their binding affinity, RMSD lower bond and RMSD upper bound, respectively: Model #1: [-6.9, 0.0, 0.0] Model #2: [-6.5, 2.576, 5.38] Model #3: [-6.5, 1.757, 3.215] Model #4: [-6.4, 2.563, 5.154] Model #5: [-6.1, 1.67, 2.537]
- Conclusion: Based on the findings from the molecular docking analysis of Cytarabine with SMO protein, it was determined that in accordance with the negative binding energy, Cytarabine can bind well to SMO protein. According to the data presented in this research, it is likely that Cytarabine is involved in regulating the SMO protein, potentially offering a novel pathway of this drug for AML treatment. Nevertheless, further investigation is still needed to determine if cytarabine has got a role in inhibiting SMO protein.
- Keywords: Cytarabine, Hedgehog pathway, SMO, Chemotherapy, AML
