Designing Potential Inhibitors Against RET PROTEIN TYROSINE KINASE DOMAIN to Fight Sporadic Medullary Thyroid Carcinoma: A Virtual Screening and Molecular Dynamics Simulation-Based Approach

Abstract

Sporadic medullary thyroid cancer (sMTC) is a rare tumor originating in the thyroid's parafollicular cells, which secrete calcitonin. Structural complexity and a significant role in thyroid carcinoma cell growth make rearranged during transfection (RET) proto-oncogene a promising target for drug discovery. This work proposes the phytochemical screening of the soursop (Annona muricata) plant to uncover and unveil the yet unrecognized potential of phytochemicals from the soursop (Annona muricata) plant as effective inhibitors against RET proto-oncogene. via molecular docking studies, pharmacokinetic property analysis, quantitative structure-activity relationship (QSAR) analysis, molecular dynamic simulation, and quantum mechanics study. Among the compounds evaluated, IMPHY010968, IMPHY012644, and IMPHY001505 have demonstrated notably stronger binding affinities compared to the conventional drug Trametinib. Their respective docking scores, namely -8.6, -8.4, and -8.1, underline their promising potential. IMPHY0012644 exhibits the maximum molar refractivity at 95.05 and possesses the highest topological polar surface area (TPSA= 107.13 Ų) compared to other compounds. In the conducted studies, all other compounds fall within the standard range of 40 ≤ MR (molar refractivity) ≤ 130, and the TPSA value is noted for its stronger correlation with the system. In the case of the ligand compound IMPHY001505, the average Root Mean Square Deviation (RMSD) ranged from 1 to 3 Å, showcasing minimal fluctuations. Likewise, IMPHY010968 and IMPHY012644 demonstrated RMSD values within the 1-5 Å range. Conversely, the control drug CID_11707110 exhibited an elevated RMSD value ranging from 1 to 8 Å, indicating more significant oscillations when compared to our proposed compound. Selected compounds exhibit greater stability when compared to the control drug. Within the 175 to 185 residue index range, the control drug displays higher fluctuations than our proposed compounds. The Rg analysis indicates that IMPHY001505, IMPHY010968, and IMPHY012644 exhibit lower Rg values than the control drug over a 100 ns period, suggesting greater compactness. SASA values imply high exposure of amino acid residues in the complexes, indicating accessibility for further analysis. MolSA reveals standard van der Waals surface areas, while PSA highlights the compounds' polar interactions with the target protein. Overall, the selected compounds display favorable structural features for potential therapeutic applications.