Repurposing of Clinically Approved Drugs to Target Smad 3 in TGF-B-mediated Epithelial Mesenchymal Transition

Song, Wei Wei (2021) Repurposing of Clinically Approved Drugs to Target Smad 3 in TGF-B-mediated Epithelial Mesenchymal Transition. [Project Paper] (Submitted)

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Abstract

Epithelial mesenchymal transition (EMT) is a process that allows epithelial cells to transform into mesenchymal cells. EMT can be divided into three main subtypes and each subtype involves different mechanisms and leads to distinct diseases. Previous studies show that transforming growth factors-β (TGF-B) is a vital inducer of type II EMT which may lead to fibrosis and organ parenchymal destruction. TGF-B signals activate and hosphorylated Smad 2 and Smad 3 that form a trimetric complex with Smad 4. This trimetric complex enters the nucleus and turns on the gene transcription of EMT. Previous studies have shown the inhibition of Smad 3 could lead to inhibition of EMT. However, there are still no clinically approved Smad 3 inhibitors in the market. Objective: This project aims to identify clinically approved drugs that reduce EMT process via Smad 3 inhibition involved in TGF-B signaling. Hypothesis: It is hypothesized that drugs with strong binding affinity to Smad 3 at MH 2 domain would inhibit its phosphorylation to stop TGF-B-mediated EMT. Methodology: The molecular structures of Smad 3 were retrieved from the Protein Data Bank (PDB). Amino acid side chain arrangements of Smad 3 were compared with the amino acid side chain arrangements of Smad 3 with the known drug binding sites found in the PDB repository using Drug Repositioning Exploration Resource (Drug ReposER). The corresponding drugs from the structurally similar known drug binding site were retrieved. Specific inhibitors of Smad 3 (SIS3) was used as a positive control in the subsequent molecular docking screening. The 3D structure of Smad 3 and selected drugs were prepared for molecular docking using the AutoDock Tool 1.5.4 (ADT). Then, search space was specified by using the AutoGrid function. Molecular docking process were performed with Autodock 4.2.6 using Lamarckan Genetic Algorithm (LGA). The drugs were ranked based on their lowest binding energies. The interaction of drugs with amino acid residue of Smad 3 were calculated using PoseView. Result and Discussion: From the screening, 94 approved drugs against the 1u7f molecule, 92 against the 1mjs molecule and 87 against the 5xoc molecule were obtained. There were only 12 drugs that have similar binding affinity and binding pose as SIS3 to the MH 2 domain of Smad 3 such as cholic acid, ketoconazole, montelukast, thioridazine, calcipotriol, bedaquiline, sapropterin, doxercalciferol, lapatinib, imatinib, bazedoxifene and indinavir. Based on previous studies, Montelukast demonstrated the reduction of the phosphorylation of Smad 3 and blocked EMT. Conclusion: Montelukast has the potential to inhibit the phosphorylation of Smad 3 and attenuate TGF-β-mediated EMT.

Item Type:	Project Paper
Faculty:	Faculty of Medicine and Health Science
Depositing User:	Ms. Nor Safa'aton Saidin
Date Deposited:	22 Aug 2023 07:52
Last Modified:	22 Aug 2023 07:52
URI:	http://psaspb.upm.edu.my/id/eprint/1119

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