The Interaction of Isoniazid on 3D Structure Variation of NAT2 Gene and Its Effect on Drug Blood Levels

Raharjo, Dian Natasya and Mutiara, Yanuar Metriks and Wahjudi, Mariana and Andrajati, Retnosari and Sartika, Ratu Ayu Dewi (2024) The Interaction of Isoniazid on 3D Structure Variation of NAT2 Gene and Its Effect on Drug Blood Levels. Journal of Medicinal and Chemical Sciences, 7 (12). pp. 1969-1981. ISSN 2651-4702

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Abstract

Drug-Resistant Tuberculosis (DR-TB) and Anti-TB Drug-Induced Liver Injury (AT-DILI) are frequently linked to polymorphisms in drug- metabolizing enzymes (DMEs). Among these, arylamine N- acetyltransferase 2 (NAT2) plays a pivotal role in metabolizing isoniazid (INH). This study investigates the structural and functional effects of NAT2 polymorphisms on INH interactions. Using the 3D structure of wild-type NAT2 (PDB ID: 2PFR) as a template, we employed Chimera, AutoDock, GROMACS, and VMD software for molecular docking and dynamic simulations. Five common coding SNPs in NAT2—G191A, T341C, G590A, A803G, and G857A—were combined to produce 15 mutant NAT2 variants. The DNA sequences of 12 TB patients from a public health center in Surabaya, Indonesia, were used to correlate acetylator phenotypes with the INH blood levels. The molecular docking analysis revealed that the binding affinity of INH to wild-type NAT2 was -5.7 kcal/mol, which is similar to most mutants. Minor variations were observed among the mutants, with affinities ranging from -5.6 to -5.7 kcal/mol. Mutants 2, 6, 8, 9, 10, 12, 14, and 15 (rapid acetylators) showed a decrease in interaction with residue G124, while new binding with residue L288 was identified in mutants 1, 3, 4, 5, and 7 (slow acetylators). These discrepancies in interactions point to a structural foundation for disparities in acetylation rates and enzyme activity. Correlations between the INH–NAT2 interaction patterns and patient acetylator phenotypes revealed distinct impacts on INH blood levels, highlighting potential implications for DR-TB treatment outcomes and AT-DILI risk

Item Type:	Article
Uncontrolled Keywords:	N-acetyltransferase 2; Isoniazid; Tuberculosis Polymorphism; Acetylator; Molecular Docking
Subjects:	T Technology > T Technology (General)
Divisions:	Faculty of Technobiology > Department of Biology
Depositing User:	Ester Sri W. 196039
Date Deposited:	17 Dec 2024 08:36
Last Modified:	17 Dec 2024 08:36
URI:	http://repository.ubaya.ac.id/id/eprint/47530

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