Publications by authors named "Hilyatuz Zahroh"

7 Publications

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Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm).

Hum Genome Var 2021 Feb 4;8(1). Epub 2021 Feb 4.

University of Patras, School of Health Sciences, Department of Pharmacy, Laboratory of Pharmacogenomics and Individualised Therapy, Patras, Greece.

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.
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http://dx.doi.org/10.1038/s41439-021-00135-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862625PMC
February 2021

Structure-based discovery of novel inhibitors of Mycobacterium tuberculosis CYP121 from Indonesian natural products.

Comput Biol Chem 2020 Apr 17;85:107205. Epub 2020 Jan 17.

Faculty of Biology, Universitas Nasional, Jakarta, 12520, Indonesia.

Tuberculosis (TB) continues to be a serious global health threat with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB). There is an urgent need to discover new drugs to deal with the advent of drug-resistant TB variants. This study aims to find new M. tuberculosis CYP121 inhibitors by the screening of Indonesian natural products using the principle of structure-based drug design and discovery. In this work, eight natural compounds isolated from Rhoeo spathacea and Pluchea indica were selected based on their antimycobacterial activity. Derivatives compound were virtually designed from these natural molecules to improve the interaction of ligands with CYP121. Virtual screening of ligands was carried out using AutoDock Vina followed by 50 ns molecular dynamics simulation using YASARA to study the inhibition mechanism of the ligands. Two ligands, i.e., kaempferol (KAE) and its benzyl derivative (KAE3), are identified as the best CYP121 inhibitors based on their binding affinities and adherence to the Lipinski's rule. Results of molecular dynamics simulation indicate that KAE and KAE3 possess a unique inhibitory mechanism against CYP121 that is different from GGJ (control ligand). The control ligand alters the overall dynamics of the receptor, which is indicated by changes in residue flexibility away from CYP121 binding site. Meanwhile, the dynamic changes caused by the binding of KAE and KAE3 are isolated around the binding site of CYP121. These ligands can be developed for further potential biological activities.
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http://dx.doi.org/10.1016/j.compbiolchem.2020.107205DOI Listing
April 2020

NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis.

Pharmacogenet Genomics 2018 07;28(7):167-176

Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo.

Background: NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group.

Objective: We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI.

Materials And Methods: Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods.

Results: The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96-2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30-5.63; P=1.76E-08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20-3.57; P=5.73E-18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B).

Conclusion: This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.
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http://dx.doi.org/10.1097/FPC.0000000000000339DOI Listing
July 2018

Immunoinformatics Approach in Designing Epitope-based Vaccine Against Meningitis-inducing Bacteria (, , and Type b).

Drug Target Insights 2016 1;10:19-29. Epub 2016 Nov 1.

Bioinformatics Research Group, Department of Chemistry, Faculty of Mathematics and Science, University of Indonesia, Indonesia.

Meningitis infection is one of the major threats during Hajj season in Mecca. Meningitis vaccines are available, but their uses are limited in some countries due to religious reasons. Furthermore, they only give protection to certain serogroups, not to all types of meningitis-inducing bacteria. Recently, research on epitope-based vaccines has been developed intensively. Such vaccines have potential advantages over conventional vaccines in that they are safer to use and well responded to the antibody. In this study, we developed epitope-based vaccine candidates against various meningitis-inducing bacteria, including , , and type b. The epitopes were selected from their protein of polysaccharide capsule. B-cell epitopes were predicted by using BCPred, while T-cell epitope for major histocompatibility complex (MHC) class I was predicted using PAProC, TAPPred, and Immune Epitope Database. Immune Epitope Database was also used to predict T-cell epitope for MHC class II. Population coverage and molecular docking simulation were predicted against previously generated epitope vaccine candidates. The best candidates for MHC class I- and class II-restricted T-cell epitopes were MQYGDKTTF, MKEQNTLEI, ECTEGEPDY, DLSIVVPIY, YPMAMMWRNASNRAI, TLQMTLLGIVPNLNK, ETSLHHIPGISNYFI, and SLLYILEKNAEMEFD, which showed 80% population coverage. The complexes of class I T-cell epitopes-HLA-C*03:03 and class II T-cell epitopes-HLA-DRB1*11:01 showed better affinity than standards as evaluated from their Δbinding value and the binding interaction between epitopes and HLA molecules. These peptide constructs may further be undergone in vitro and in vivo testings for the development of targeted vaccine against meningitis infection.
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http://dx.doi.org/10.4137/DTI.S38458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091093PMC
November 2016

Screening Analogs of β-OG Pocket Binder as Fusion Inhibitor of Dengue Virus 2.

Drug Target Insights 2015 16;9:33-49. Epub 2015 Nov 16.

Mathematics Computation Research Group, Faculty of Mathematics and Science, Department of Mathematics, University of Indonesia, Jawa Barat, Indonesia.

Dengue is an infectious disease caused by dengue virus (DENV) and transmitted between human hosts by mosquitoes. Recently, Indonesia was listed as a country with the highest cases of dengue by the Association of Southeast Asian Nations. The current treatment for dengue disease is supportive therapy; there is no antiviral drug available in the market against dengue. Therefore, a research on antiviral drug against dengue is very important, especially to prevent outbreak explosion. In this research, the development of dengue antiviral is performed through the inhibition of n-octyl-β-D-glucoside (β-OG) binding pocket on envelope protein of DENV by using analogs of β-OG pocket binder. There are 828 compounds used in this study, and all of them were screened based on the analysis of molecular docking, pharmacological character prediction of the compounds, and molecular dynamics simulation. The result of these analyses revealed that the compound that can be used as an antiviral candidate against DENV is 5-(3,4-dichlorophenyl)-N-[2-(p-tolyl) benzotriazol-5-yl]furan-2-carboxamide.
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http://dx.doi.org/10.4137/DTI.S31566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651419PMC
November 2015

Ultrasonically enhanced extraction of luteolin and apigenin from the leaves of Perilla frutescens (L.) Britt. using liquid carbon dioxide and ethanol.

Ultrason Sonochem 2016 Mar 24;29:19-26. Epub 2015 Aug 24.

Faculty of Science and Technology, Syarif Hidayatullah State Islamic University (UIN) Jakarta, JL.Ir.H.Juanda Ciputat, Tangerang, Indonesia.

The present study reports on the ultrasonic enhancement of the liquid carbon dioxide (CO2) extraction of luteolin and apigenin from the leaves of Perilla frutescens (L.) Britt., to which ethanol is added as a cosolvent. The purpose of this research is also to investigate the effects of the particle size, temperature, pressure, irradiation power, irradiation time, and ethanol content in the liquid CO2 solution on the extraction yield using single-factor experiments. We qualitatively and quantitatively analyzed the yields in the extract using HPLC (high-performance liquid chromatography). The liquid CO2 mixed with ethanol was used at temperatures of 5, 20 and 25 °C with extraction pressures from 8 to 14 MPa. The yields of luteolin and apigenin in the extraction were clearly enhanced by the ultrasound irradiation, but the selectivity of the extract was not changed. The yields of luteolin and apigenin in the extract were also significantly improved by adjusting the operating temperature, the irradiation time, and the ethanol content in the liquid CO2 solution, but no change in the selectivity of the extract was observed.
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http://dx.doi.org/10.1016/j.ultsonch.2015.08.016DOI Listing
March 2016

Screening of commercial cyclic peptide as inhibitor NS5 methyltransferase of Dengue virus through Molecular Docking and Molecular Dynamics Simulation.

Bioinformation 2014 29;10(1):23-7. Epub 2014 Jan 29.

Department of Chemistry, Faculty of Mathematics and Natural Science, University of Indonesia, Depok 16424 Indonesia.

Dengue has become a major global health threat, especially in tropical and subtropical regions. The development of antiviral agent targeting viral replication is really needed at this time. NS5 methyltransferase presents as a novel antiviral target. This enzyme plays an important role in the methylation of 5'-cap mRNA. Inhibition of the NS5 methyltransferase could inhibit dengue virus replication. In this research, two sites of NS5 methyltransferase (S-Adenosyl methionine/SAM binding site and RNA-cap site) were used as targets for inhibition. As much as 300 commercial cyclic peptides were screened to these target sites by means of molecular docking. Analysis of ligand-enzyme binding free energy and pharmacological prediction revealed two best ligands, namely [Tyr123] Prepro Endothelin (110-130), amide, human and Urotensin II, human. According to molecular dynamic simulation, both ligands maintain a stable complex conformation between enzyme and ligand at temperature 310 K and 312 K. Hence, Urotensin II, human is more reactive at 312 K than at 310 K. However, both ligands can be used as potential inhibitor candidates against NS5 methyltransferase of dengue virus with Urotensin II, human exposes more promising activity at 312 K.
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http://dx.doi.org/10.6026/97320630010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916815PMC
February 2014
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