IN SILICO STUDY OF SIRT1 ACTIVATORS USING A MOLECULAR DYNAMIC APPROACH

azmina, azminah (2019) IN SILICO STUDY OF SIRT1 ACTIVATORS USING A MOLECULAR DYNAMIC APPROACH. International Journal of Applied Pharmaceutics, 11 (1). pp. 237-245. ISSN 0975-7058

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Abstract

Objective: The importance of SIRT1 activator’s role in antidiabetic and anti-aging therapies is widely demonstrated. Drug discovery and development are time consuming. Drug design can be performed in silico using molecular dynamic approaches to accelerate and facilitate identification of the best compound candidates and their physicochemical characteristics and hit-to-lead selection.Methods: In silico study of SIRT1 activator for complexes using of Protein Data Bank (PDB) IDs 4ZZI, 4ZZJ 4ZZH, and 5BTR and 4TO ligand. Ligand–receptor interactions and bond energies were determined using molecular docking with the AutoDock4Zn program. Then, the complex with the best bond energy was identified using a simulation of the molecular dynamics (50 ns) using the Amber program, and values for root mean square deviation, root mean square fluctuation, and bond energy were determined using the Molecular Mechanic–Poisson Boltzmann (Generalized Born) surface area (MM-PB[GB]SA) calculation.Results: Interaction analysis between activator ligand (4TO) and the SIRT1 receptor (PDB IDs 4ZZJ and 5BTR) revealed the ligand’s selectivity for hydrophobic interaction at Leu206, Ile223, Ile227, and hydrophilic interaction at Asn226, Glu230. Hydrogen bond interactions between Glu230 and Arg234 (allosteric region) with Arg446, Val459, His473, and Asp475 (catalytic region) brought them close to the bounding substrate area. Bond energy values obtained using the MM-GB(PB)SA calculation showed 4TO interaction with 4ZZJ (MMGBSA ∆G, −31.4729–−26.6756; MMPBSA ∆G, −32.6292–−28.486]. The bond energy value of the 4TO interaction with 5BTR showed MMGBSA ∆G = −40.6255–−30.0653 and MMPBSA ∆G = −34.6713–−25.9951.Conclusions: These findings provide important information on the target interaction of the bonds to the more selective SIRT1 activator useful for drug discovery and development. Keywords: SIRT1 activator, Molecular docking, Molecular dynamic, Molecular mechanic/Poisson Boltzmann (generalized born) surface area.

Item Type: Article
Uncontrolled Keywords: SIRT1 activator, Molecular docking, Molecular dynamic, Molecular mechanic/Poisson Boltzmann (generalized born) surface area
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Pharmacy > Department of Pharmacy
Depositing User: AZMINAH 204031
Date Deposited: 08 Jul 2019 06:58
Last Modified: 08 Jul 2019 06:58
URI: http://repository.ubaya.ac.id/id/eprint/34987

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