Kanker lambung disebabkan oleh mutasi gen pada protein p53 dan EGFR, yang mengganggu fungsi normal kedua protein tersebut dalam mengatur proliferasi dan apoptosis sel. Salah satu kelompok senyawa yang berpotensi mengembalikan fungsi p53 dan EGFR adalah turunan quinazolina. Senyawa ini telah banyak diteliti karena aktivitas biologisnya yang luas, termasuk sebagai agen antikanker. Untuk menilai potensi interaksinya dengan p53 dan EGFR, senyawa turunan quinazolina dianalisis sebagai kandidat senyawa antikanker lambung. Evaluasi dilakukan menggunakan pendekatan in silico, seperti penambatan molekul dan simulasi dinamika molekul, yang dapat memprediksi potensi interaksi ligan terhadap protein target.
Modifikasi struktur senyawa turunan quinazolina dilakukan berdasarkan hasil penambatan molekul terhadap protein reseptor p53 dan EGFR. Proses penambatan molekul menggunakan perangkat lunak YASARA dan divalidasi melalui penambatan ulang sebanyak 100 kali. Hasil validasi menunjukkan nilai RMSD kurang dari 2.
Tiga senyawa hasil modifikasi turunan quinazolina dengan hasil penambatan molekul terbaik adalah: (E)-2-(2,4-dinitrostiril)-4-(4-aminobutil)aminoquinazolina (Q-2), (E)-2-(3-siano-4-nitrostiril)-4-(4-aminobutil)aminoquinazolina (Q-4), dan (E)-2-(3-trifluorometil-4-nitrostiril)-4-(4-aminobutil)aminoquinazolina (Q-9). Ketiga senyawa tersebut memiliki interaksi hidrogen konvensional dengan residu asam amino katalitik utama Val147 pada p53, dengan energi ikat sebesar -8,3120; -8,1330; dan -8,1240 kkal/mol. Senyawa-senyawa tersebut juga memiliki interaksi hidrogen konvensional dengan residu asam amino katalitik utama Asp831 pada EGFR, dengan energi ikat sebesar -8,7090; -8,7800; dan -9,1060 kkal/mol. Simulasi MD menunjukkan ligan Q-2 pada p53 dan Q-9 pada EGFR membentuk kompleks ligan-protein yang paling stabil. Analisis ADMET dari Q-2, Q-4, dan Q-9 menunjukkan sifat farmakokinetika yang baik. Berdasarkan analisis tersebut, maka senyawa usulan Q-2 dan Q-9 dapat dijadikan sebagai kandidat antikanker lambung.
Gastric cancer is caused by gene mutations in the p53 and EGFR proteins, which disrupt the normal functions of these proteins in regulating cell proliferation and apoptosis. One group of compounds with the potential to restore the function of p53 and EGFR is quinazoline derivatives. These compounds have been extensively studied due to their broad biological activities, including their role as anticancer agents. To assess their interaction potential with p53 and EGFR, quinazoline derivatives were analyzed as candidate compounds for gastric cancer therapy. The evaluation was carried out using in silico approaches, such as molecular docking and molecular dynamics simulation, which can predict the potential interactions of ligands with their target proteins.
Structural modifications of the quinazoline derivatives were performed based on the results of molecular docking against p53 and EGFR receptor proteins. Molecular docking was conducted using YASARA software and validated through 100 redocking iterations. The validation results showed RMSD values of less than 2 Å and similar interaction patterns to the crystallographic data, indicating that the docking method was valid and reliable.
The three best docking structures were further evaluated for their stability using molecular dynamics simulations and assessed for pharmacokinetic properties using ADMET analysis.
The three best-modified quinazoline derivatives based on molecular docking results were: (E)-2-(2,4-dinitrostyryl)-4-(4-aminobutyl)aminoquinazoline (Q-2), (E)-2-(3-cyano-4-nitrostyryl)-4-(4-aminobutyl)aminoquinazolina (Q-4), and (E)-2-(3-trifluoromethyl-4-nitrostyryl)-4-(4-aminobutyl)aminoquinazoline (Q-9). These compounds exhibited conventional hydrogen bond interactions with the key catalytic residue Val147 of p53, with binding energies of -8.3120, -8.1330, and -8.1240 kcal/mol, respectively. They also formed conventional hydrogen bonds with the key catalytic residue Asp831 of EGFR, with binding energies of -8.7090, -8.7800, and -9.1060 kcal/mol, respectively. MD simulations revealed that ligand Q-2 in complex with p53 and Q-9 in complex with EGFR formed the most stable ligand–protein interactions. Furthermore, ADMET analysis of Q-2, Q-4, and Q-9 demonstrated favorable pharmacokinetic properties. Based on these findings, Q-2 and Q-9 are proposed as potential candidates for the development of gastric anticancer agents.
Kata Kunci : Quinazolina, kanker lambung, p53, EGFR, penambatan molekul, dinamika molekul
