• Novel Irinotecan-SMO affinity: Comparing with Glasdegib in AML's Hedgehog pathway via Molecular Docking
  • Melika Naderi,1,*
    1. Tehran Medical Sciences, Islamic Azad University, Tehran, Iran


  • Introduction: Acute myeloid leukemia (AML) is a multifactorial type of cancer characterized by the rapid growth of abnormal white blood cells. Amongst several pathways implicated in the development of AML, dysregulation of the hedgehog pathway can be a hallmark as it's a crucial signaling system in cell differentiation and proliferation. Recent studies suggest that the aberrant activation of the Hedgehog pathway is linked to the evolution and progression of leukemia, particularly leading to uncontrolled cell growth. One key player in the Hedgehog pathway is the Smoothened (SMO) protein, which regulates downstream signaling. Glasdegib is shown to inhibit tumor growth by targeting the Hedgehog pathway via blocking the activity of SMO in AML. Furthermore, Irinotecan known as a chemotherapeutic agent, exerts its antitumor effects by inhibiting the activity of topoisomerase I. Also, Irinotecan is an effective treatment option for leukemia, not yet been discovered whether it affects the hedgehog pathway or not. The objective of this study is to evaluate the affinity of Irinotecan to SMO protein in comparison with Glasdegib and to hypothesize the probable association of Irinotecan through the hedgehog pathway in leukemia.
  • Methods: In this research, at first, the SMO protein structure was downloaded from the Uniprot website, then necessary preparations, including adding charge and hydrogen ions, were performed using Chimera software. The three-dimensional structures of Irinotecan and Glasdegib were obtained 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 assess the binding status of Irinotecan and Glasdegib to SMO protein.
  • Results: Following the completion of the docking process of Irinotecan and Glasdegib with SMO protein, using PyRx software, the achieved results are summarized below. For each Model, the data represents their binding affinity, RMSD lower bond and RMSD upper bound, respectively: Irinotecan: Model #1: [-7.8, 0.0, 0.0] Model #2: [-7.5, 7.93, 11.76] Model #3: [-7.1, 2.668, 11.684] Glasdegib: Model #1: [-6.3, 0.0, 0.0] Model #2: [-6.2, 6.021, 8.538] Model #3: [-6.2, 5.65, 10.073]
  • Conclusion: Based on the findings from the molecular docking analysis of Irinotecan and Glasdegib with SMO protein, it was determined that both drugs exhibit negative binding energy. Additionally, Irinotecan showed a stronger affinity compared to Glasdegib. According to the data presented in this research, it is likely that Irinotecan 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 Irinotecan has got a role in inhibiting SMO protein even greater than Glasdegib.
  • Keywords: Irinotecan, Hedgehog pathway, SMO protein, Glasdegib, AML