Firdayani Firdayani

OBJECTIVE Atopic dermatitis (AD) is a complex inflammatory skin disorder with a strong genetic component. Identifying missense variants with functional relevance is essential for understanding disease mechanisms and informing therapeutic development. This study identified functionally relevant SNPs for AD using integrated genomic and bioinformatics analyses. METHODS We screened 180 AD-associated SNPs from the GWAS Catalog and filtered missense variants with genome-wide significance. Functional impact was assessed using PolyPhen-2 and Sorting Intolerant From Tolerant (SIFT). Population allele frequencies were extracted from the 1000 Genomes Project, tissue expression profiles from the GTEx Portal, and drug–gene interactions from DGIdb. RESULTS Two prioritized missense variants were identified: rs2228145 in IL6R, a common benign variant that modulates IL-6 signaling, and rs183884396 in TESPA1, a rare variant predicted to be damaging and enriched in European populations. TESPA1 showed minimal expression in healthy skin but substantial expression in immune-relevant tissues, suggesting an indirect immunoregulatory role in AD. IL6R demonstrated broad immune-tissue expression and multiple interactions with approved anti-inflammatory drugs, underscoring its therapeutic relevance. CONCLUSION By integrating genomic, functional, and pharmacological data, this study highlighted TESPA1 as a biologically plausible yet understudied immunoregulatory gene and IL6R as a clinically actionable target in AD. These computational findings are hypothesis-generating and warrant experimental validation to elucidate variant-specific mechanisms. Importantly, the identification of IL6R-targeting drugs and the ancestry-specific nature of TESPA1 variation provides a foundation for future precisionmedicine approaches in AD.

The fatty liver disease known as steatohepatitis is characterized by liver inflammation. De novo lipogenesis and mevalonate pathway have been identified as contributing to the development of fatty liver. Rheum genus has pharmacological properties such as antioxidant, anti-inflammatory, hepatoprotective, and hypolipidemic. Consequently, the current study investigated bioactive compounds from Rheum genus using in-silico method. The 109 compounds and their natural inhibitors against the enzyme targets ATP-citrate lyase (ACLY), Acetyl-CoA carboxylase (ACC), Fatty Acid Synthase (FASN), Stearoyl-CoA desaturase (SCD1), and HMG-CoA reductase (HMGCR) were performed. The results obtained are in the form of a re-rank score, with the best compound results for each enzyme is Catechin 7,3'-di-O-β-D-glucopyranoside (A1) (-148.73), 4' - Methoxy - 3, 3',5 - trihydroxystilbene' - O - β – D (2"-O-p-coumaryl) - glucopyranoside (A2) (-136,808), 2-Cinnamoyl-1,6-digalloyl glucose (A3) (-149,589), 3-O-Galloyl Epicatechin (A4) (-160,018), and 6-C-Glucopyranosyl Procyanidin B2 (A5) (-84,843) as ACLY, ACC, FASN, SCD1 and HMGCR inhibitors, respectively. Analyses using the ADMET and Lipinski rules revealed that A4 has the potential to be a lead compound for oral drug use, but more research is required.

Cyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing pro-inflammatory eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom’s leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom’s alkaloid extract containing ~ 46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10–46% viability at 50–100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom’s leaf containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-α (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom’s alkaloids to have great potential dual inhibition activity towards COX-2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.

Cyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a crucial role in the production of pro-inflammatory eicosanoids, including prostaglandins and leukotrienes (LTs) via arachidonic acid (AA) pathways. Non-steroidal anti-inflammatory drugs (NSAIDs) typically work by inhibiting COX enzymes (COX-1, COX-2) to alleviate inflammatory responses in our bodies. However, the use of these selective COX inhibitors results in an upregulation of the AA pathway. This condition stimulates the LOX enzymes to increase LT production, exacerbating the severity of the disorders. In this study, the alkaloid extract derived from the leaf of Mitragyna speciosa (Kratom) demonstrated a dual inhibitory effect on COX-2/5-LOX enzymes in lipopolysaccharides (LPS)-induced RAW 264.7 macrophage cells. The alkaloid extract containing ~ 46% mitragynine inhibited COX-2 and 5-LOX activity at concentrations of less than 25 ppm with no toxicity to the cells. Above 25 ppm, the alkaloid extract exhibited toxicity to the cells (e.g,, ~ 46% viability at 50 ppm) and only inhibited COX-2 activity. In contrast, the Kratom crude extract containing ~ 5% mitragynine did not inhibit COX-2 or 5-LOX activity in LPS-induced RAW 264.7 macrophage cells at more than 25 ppm and did not exhibit toxicity to the cells even at 100 ppm. The alkaloid compounds in the Kratom leaf are likely responsible for this activity, as the alkaloid extract containing these biomolecules suppressed reactive oxygen species (ROS), nitric oxide (NO), inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Molecular studies also suggested a strong binding affinity of Kratom alkaloids to the active sites of COX-2 and 5-LOX. The dual inhibitory activity of the Kratom alkaloids against COX-2 and 5-LOX provides insights into their potential as safer NSAIDs.

The human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) plays a significant role in viral replication and is one of the targets for anti-HIV. However, a mutation in viral strains rapidly developed the resistance of the com-pounds to the protein, reducing the effectiveness of the inhibitors. This work seeks to utilize machine learning-based quantitative structure-activity relationship (QSAR) analysis in combination with molecular docking simulations to forecast the presence of active compounds derived from medicinal plants. Specifically, the objective is to identify com-pounds that have the potential to operate as inhibitors of HIV-1 reverse transcriptase (RT), encompassing both wild-type and mutant variants. It is demonstrated that some substances are no longer suitable as inhibitors due to changes in the HIV-1 RT enzyme. Based on the screening results, four medicinal plants, Melissa officinalis, Punica granatum, Psidium guajava, and Curcuma longa, are worth further investigation. Nevertheless, the findings from the in vitro study suggest that extracts derived from pomegranate rind and guava leaves exhibit significant promise as HIV-1 RT inhibitors.

Background/aim: Tuberculosis has still become the most deadly disease globally. The problem of finding an effective therapeutic is one of the obstacles in the treatment of patients. Marine invertebrates were a treasure since they produced many active compounds. Following up on this issue, screening active compounds is very important. This study will explain the result of anti-tuberculosis screening of compounds derived from marine invertebrates using in silico and confirmed to the in vitro-data.Materials and methods: Three-dimensional (3D) structures of pantothenate kinase (MtPanK type 1, PDB ID: 4BFT), Mycobacterium tuberculosis InhA (MtInhA, PDB ID: 2X23), protein kinase B (PDB ID: 5U94), and β-ketoacyl acyl carrier protein synthase I (MtKasA, PDB ID: 2WGE) were used as protein targets. Confirmation of in-vitro studies was done to the potential marine sponges as the targeted compounds. Results: The molecular docking analysis showed that the lowest docking scores were: 19-hydroxypsammaplysin Q against MtPank type 1 (-129.956), 19-hydroxypsammaplysin S towards MtInhA (-131.310), psammaplysin L against protein kinase B (-121.875), and psammaplysin K dimethoxy acetal against MtKasA (-127.916), while no reported in-vitro data supported yet. However several compounds such as molamide C and manzamine group are also on the top ten docking scores and the previous in vitro evaluation showed potential antituberculosis compounds. The preliminary in-vitro study of a compound derived from the genus Pseudoceractina that related to psammaplysins through bromotyrosine pathway was subereamide A. It showed activity against Mycobacterium smegmatis with MIC values comparable to the rifampicin. This data was also supported by the molecular docking score of subereamide A which was insignificant to the psammaplysin groups. Conclusion: This study proved that psammaplysin group, subereamide A, mollamide C and achantomanzamine have potential as anti-TB compounds. A further analysis of compounds derived from the Verongiidae family will be done to confirm the detailed in silico data.

Emodin (6-methyl-1,3,8-trihydroxyanthraquinone) is a natural anthraquinone derivative with potential pharmacological such as cytotoxic effects. The structure modification could be performed to determine the functional groups that have the role of substance activities. In this study, we modified one hydroxy group in the emodin structure to become dimethyl carbamoyl moiety. Emodin was reacted with dimethyl carbamoyl chloride and potassium carbonate to create 3-dimethyl carbamoyl emodin. The structure of the product was elucidated using mass spectrophotometer (MS), Fourier transform infrared (FTIR), proton and carbon nuclear magnetic resonance (H-NMR and C-NMR). These substances were tested for cytotoxicity against HepG2 cell lines using the MTT assay. According to the evaluation, 3-dimethyl carbamoyl emodin is less cytotoxic than emodin. As a result, the hydroxy group at the C3 position of emodin has been identified as a functional component that contributes to its cytotoxic effect.

Breast cancer ranks as the second leading cause of death among women, but early screening and self-awareness can help prevent it. Hormone therapy drugs that target estrogen levels offer potential treatments. However, conventional drug discovery entails extensive, costly processes. This study presents a framework for analyzing the quantitative structure–activity relationship (QSAR) of estrogen receptor alpha inhibitors. Our approach utilizes supervised learning, integrating self-attention Transformer and molecular graph information, to predict estrogen receptor alpha inhibitors. We established five classification models for predicting these inhibitors in breast cancer. Among these models, our proposed MATH model achieved remarkable precision, recall, F1 score, and specificity, with values of 0.952, 0.972, 0.960, and 0.922, respectively, alongside an ROC AUC of 0.977. MATH exhibited robust performance, suggesting its potential to assist pharmaceutical and health researchers in identifying candidate compounds for estrogen alpha inhibitors and guiding drug discovery pathways.

Emodin (1,3,8-trihydroxy-6-methyl-9,10-anthraquinone) is an anthraquinone bioactive compound used as a lead compound because it exhibits potential anticancer properties. Structural modifications were made at the C3 position and its relationship to cytotoxic activity against the HepG2 cell line to determine the pharmacophore group of this compound. The hydroxy group at C3 emodin is converted to an ester group to produce 3-acetyl emodin. In addition, docking simulations into the cancer target protein casein kinase-2 were also carried out to predict molecular interactions. Emodin was reacted with anhydrous acetate and confirmed the product confirmation using LCMS/MS, FTIR, 1H-NMR, and 13C-NMR. Emodin and 3-acetyl emodin were tested for cytotoxicity against HepG2 cells in vitro. Cytotoxic emodin and 3-acetyl emodin tests on HepG2 cells resulted in Cytotoxic concentrations 50 (CC50) of 0.54 mM and 0.42 mM, respectively. The results showed that modifying the C3 hydroxyl group with acetyl can increase the cytotoxic effect more than emodin. This research is expected to provide information regarding the structure-activity relationship of emodin in cancer cells and the expansion of new drug applications for additional cancers.