Dynamic of Mutant p53 Reactivation by Maleimide Analogues

Wibowo, Fajar Rakhman and Hidayat, Yuniawan and Wartono, Muhammad Widyo (2014) Dynamic of Mutant p53 Reactivation by Maleimide Analogues. IbM.

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    Abstract

    Apoptosis, a programed cell death is promising target for drug development in spe¬cific chemotherapy. Reactivation of mutant p53-tumor-suppressor leads to massive apop¬tosis as more than 50% of human tumor cells loss its p53 function due to the mutation. Several small molecules (e.g. PRIMA-1 and maleimide analogues) have demonstrated a restoration of wild-type p53 expression. The restoration triggers cell death and elimi-nates tumors in vivo. Recently, molecular mechanism of restoration was partly discovered. Adducts formation of converted PRIMA-1 with thiols in mutant p53 is sufficient to induce apoptosis in tumor cells. In order to contribute on the mechanism of p53 restoration study, we have performed in total of more than 800 ns molecular dynamics simulations of p53 and it complexes with small ligand. These simulations results in total about 1 terabyte data. Early evaluation of these trajectories has demonstrated that the dynamics properties of p53 at difference mutation state might responsible for their ability to bind to its DNA target. Maleimide analogues were able to induce an alteration of p53 dynamics. However we still lack of information for the necessity of the adduct formation. We were also working on the formation of this type of adduct by means of quantum mechanic calculation and prepare for MD simulation of the formed adduct. Apoptosis, kematian sel terprogram merupakan target yang menjanjikan untuk reka-yasa obat kemoterapi yang spesifik. Reaktivasi mutant p53-tumor-suppressor memicu terjadinya apoptosis massal mengingat lebih dari 50% sel tumor kehilangan fungsi p53 akibat mutasi. Beberapa molekul kecil (contohnya: PRIMA-1 dan turunan maleimida) telah menunjukkan kemampuannya mengembalikan ekspresi wild-type p53. Pengembalian fungsi p53 akan memicu kematian sel dan menghilangkan tumor in vivo. Baru-baru ini, mekanisme pengembalian fungsi pada tingkat molekuler mulai terungkap. Pembentukan kompleks adduct dari PRDVIA-1 terkonversi dengan tiol dari p53 termutasi cukup untuk menginduksi apoptosis dalam tumor sel. Total simulasi dinamika molekuler sepanjang 800 ns telah kami lakukan untuk memberikan kontribusi dalam studi mekanisme pengem¬balian fungsi p53. Simulasi yang telah dilakukan menghasilkan data sebesar kurang lebih 1 terabyte. Eva-luasi awal dari trajektori-trajektori tersebut menunjukkan bahwa sifat di-namis p53 pada status mutasi yang berbeda akan menentukan kemampuannya berinter-aksi dengan DNA targetnya. Turunan maleimida dapat mengubah dinamika p53. Namun kami masih belum memiliki cukup informasi tentang pentingnya pembentukan adduct. Kami juga mempelajari pembentukan adduct menggunakan metode mekanika kuantum dan mempersiapkan simulasi DM dari adduct yang terbentuk.

    Item Type: Article
    Subjects: R Medicine > R Medicine (General)
    Divisions: Lembaga Penelitian dan Pengabdian Kepada Masyarakat - LPPM
    Depositing User: Lia Primadani
    Date Deposited: 15 Apr 2014 00:51
    Last Modified: 01 Sep 2016 13:13
    URI: https://eprints.uns.ac.id/id/eprint/11007

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