KESIMPULAN DAN SARAN

KESIMPULAN DAN SARAN

A. Kesimpulan

1. Kerapatan elektron ikatan rangkap C-C MIRA-1 dapat menjadi asimetris dengan adanya pengaruh induksi dari gugus – gugus asam amino dan rantai samping MIRA-1.

2. Ikatan rangkap MIRA-1 dapat terpolarisasi sebagai pengaruh dari lekukan mutasi. Atom O karbonil dari ikatan peptida yang dekat dengan atom O karbonil bagian maleimida dapat menginduksi atom O tersebut untuk memberikan tarikan elektron yang lebih besar sehingga ikatan rangkap C-C kerapatan elektronnya semakin rendah dan dapat terpolarisasi. Polarisasi memberikan kemudahan serangan gugus tiol yang mengindikasi kebolehjadian yang tinggi pada pembentukan adduct tiol.

3. Bagian alifatik MIRA-1 mempunyai gugus karbonil yang memudahkan untuk mendapat induksi dari asam amino yang menjadikan kerapatan elektron ikatan rangkap C-C menjadi rendah dan mempunyai tingkat polarisasi tinggi. Bagian alifatik bersifat fleksibel dapat bergerak pada posisi tertentu dan menyebabkan ikatan rangkap C-C mempunyai kerapatan elektron yang berbeda antar atom C-nya.

B. Saran

Perlunya dilakukan studi interaksi dengan memperbanyak variasi konformasi kompleks p53 termutasi Y220C dengan MIRA-1.

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Alberts, B, A. Johnson, J. Lewis, M. Raff. 2002. Molecular Biology of the Cell,

4th Edition . Garland Science, New York.

Basse, N, J. L. Kaar, G. Settani, A.C. Joerger, T.J. Rutherford, and A.R. Fersht.

2010. Toward the Rational Design of p53-Stabilizing Drugs: Probing the Surface of the Oncogenic Y220C Mutant. Chem and Biol, 17: pp. 46-56.

Boeckler, F. M, A.C. Joerger, G. Jaggi, T.J. Rutherford, D.B. Veprintsev, and

A.R. Fersht. 2008. Targeted Rescue of a Destabilized Mutant of p53 by an in Silico Screened Drug. Proc. Natl. Acad. Sci. USA 105: pp. 10360 – 10365.

Bullock, A. N, J. Henckel, and A.R. Fersht. 2000. Quantitative Analysis of Asam

aminoal Folding and DNA Binding in Mutant p53 Core Domain: Definition of Mutant States for Rescue in Cancer Therapy. Oncogene 19: pp.1245-1256.

Bykov, V. J. N, N. Issaeva, G. Selivanova, and K. G. Wiman. 2002a. Mutant p53-

Dependent Growth Suppression Distinguishes PRIMA-1 From Known Anticancer Drugs: A Statistical Analysis of Information In The National Cancer Institute Database. Carcinogenesis. 23(12): pp.2011 –2018.

Bykov, V. J. N, N. Issaeva, A. Shilov, M. Hultcrantz, E. Pugaekeva, P.

Chumakov, J. Bergman, K.G. Wiman, G. Selinanova. 2002b. Restoration of the Tumor Suppresor Function to Mutant p53 by A Low-Molecular Weight Compound. Nature Medicine. 8(3): pp.282 – 288.

Bykov, V. J. N, N. Issaeva, N. Zache, A. Shilov, M. Hultcrantz, J. Bergman, G.

Selinanova, and K.G. Wiman. 2005. Reactivation of Mutant p53 and

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Biol Chem , 280(34): pp. 30384 – 30391.

Copeland, Robert. A. 2000. Enzymes : A Practical Introduction to Structure,

Mechanism, and Data Analysis . Second Edition. New York:John Wiley & Sons,Inc.

Das, D, P. Kirsten, M.B. Eric, S. Paul, C.C. David, H. Milan, and R.B. Bernard.

2002. Optimization of Quantum Mechanichal Molecular Mechanical Partitioning Schemes : Gaussian Delocalization of Molecular Mechanical Charges and The Double Link Atom Method. J Chem Phys, 117:10535- 10547.

Dolenc, J, and J. Koller. 2006. An Improved Semiempirical MO PM3 Method for Hydrogen-Bonded Systems. Acta Chim. Slov.53: 229 –237.

Dorsett, H, and A. White. 2000. Overview of Molecular Modelling and Ab initio

Molecular Orbital Methods Suitable for Use with Energetic Materials. DSTO Aeronautical and Maritime Research Laboratory, Australia.

Effendy. 2005. Teori VSEPR Kepolaran dan Gaya Antarmolekul. Edisi ke-2.

Bayumedia, Malang. Frisch, A, J.F. Michael, and W.T. Gary. 2003. Gaussian 03 User’s Reference.

Wallingford. Gaussian, Inc. Glendening, D. Eric, R.L. Clark, and W. Frank. 2011. Natural Bond Orbital

Methods. Comput Mol Sci 00: 1-42. Humphrey, W, A. Dalke, and K. Schulten. 1996. VMD -Visual Molecular

Dynamics. J. Molecular Graphics 14: pp. 33-38. Joerger, A. C, H. C. Ang, and A. R. Fersht. 2006. Structural Basis for

Understanding Oncogenic p53 Mutations and Designing Rescue Drugs. Proc. Natl. Acad. Sci . USA 103: pp. 15056 –15061.

commit to user

of common p53 cancer mutants. Oncogene 26: pp.2226 –2242. Lambert, J. M. R, P. Gorzov, D. B. Veprintsev, M. Soderqvist, D. Segback, J.

Bergman, A.R. Fersht, P. Hainaut, K.G. Wiman, and V.J.N. Bykov. 2009. PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain. Cancer Cell. 15: 376 –388.

Laue, T. and A. Plagens. 2005. Named Organic Reactions. Second Edition. John

Willey & Sons Ltd., England. Leach, A. R. 2001. Molecular Modelling: Principles and Applications. Second

Edition. Prentice-Hall, USA. Lee, T, and P.A. Kollman. 1999. Quantum Mechanical Calculations of

Nucleophilic Attack in the Pseudouridine Synthesis Reaction. J. Am. Chem. Soc. 121: 9928-9931.

Liu, H, M. Elstner, E. Kaxiras, T. Frauenheim, J. Hermans, and W. Young. 2001.

QuantumMechanics Simulation of Protein Dynamics on Long Timescale. Protein Struc Funct Genet . 44: 484 –489.

Manikrao, A.M, N.S. Mahajan, and R.D. Jawrkar. 2011. Docking Studies of few

C-3 Substituted Azapteridines as Hepatitis C Virus RNA-Dependent RNA Polymerase inhibitors. J. Comput. Method. Mol. Design. 1(4): 35-45.

March, J. 1968. Advanced Organic Chemistry: Reactions, Mechanism, and Structure. International Student Edition. Japan: McGraw-Hill, Inc.

Monajjemi, M, B. Honaparvar, B. Khalili, A.R. Iikhani, and F. Mollaamin. 2010.

Thermo-Chemical Investigation and NBO Analysis of Some Anxileotic as Nano-Drugs. J Pharmacy and Pharmacology, 4(8): 521-529.

commit to user

Chimera – A Visualization System for Exploratory Research and Analysis. J. Comput. Chem ., 25(13): pp.1605-1612.

Pudjaatmaka, A. H. 1999. Kimia Organik. Jilid 2. Edisi Ketiga. Erlangga, Jakarta,

Terjemahan: Organic Chemistry. Fessenden, R. J. & J. S. Fessenden. 1986. Wadsworth, Inc., USA.

Rauk, A. 2001. Orbital Interaction Theory of Organic Chemistry. Second Edition.

John Wiley & Sons,Inc., New York. Schaftenaar, G, and J. H. Noordik. 2000. Molden: A Pre- and Post-Processing

Program for Molecular and Electronic Structures. J. Comput.-Aided Mol. Design , 14: pp. 123-134.

Thiel, W. 2009. QM/MM Methodology: Fundamentals, Scope, and Limitations

dalam J. Grotendorst, N. Attig, S. Blugel, D. Marx. Multiscale Simulation Methods in Molecular Sciences. Institute for Advanced Simulation, Forschungszentrum Julich.

Wiman, K. G. 2010. Pharmacological Reactivation of Mutant P53: From Protein

Structure to the Cancer Patient. Oncogene. 29: 4245 –4252. Young, D. C. 2001. Computational Chemistry: A Practical Guide for Applying

Techniques to Real-World Problems. John Wiley & Sons, Inc., New York.

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Lampiran 1. Perhitungan nilai ∆occupancy ikatan rangkap C-C MIRA-1

Nilai occupancy ikatan rangkap C-C