Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 22, Issue 1, 2025

Mycobacterium tuberculosis (Mtb) is the primary cause of infectious tuberculosis (TB) and is primarily spread through respiratory droplets. TB is an ancient disease discovered a century ago, and still despite all the advances in the medical sciences, this disease continues to be one of the top 10 diseases. WHO reported that in 2024, 10.6 million people were infected with TB, and 1.6 million fatalities were linked to the disease. The conventional TB treatment encompasses the use of antimicrobial drugs, but due to shortcomings like the emergence of antimicrobial resistance, lengthy treatment protocols, side effects, and drug tolerance, antimicrobial therapies are not yielding successful outcomes in TB treatment. Therefore, an alternate approach to the conventional TB treatment protocol is warranted.

A meticulous evaluation of scientific, qualitative, and quantitative research from the most prominent scientific databases was carried out. We searched Embase, Scopus, Web of Science, Google Scholar, and PubMed literature on TB management up to date. The present study discusses immunotherapy and drug repurposing as emerging potential alternate treatment options for combating TB. This study examines TB resistance, the immunotherapy approach, and the mechanism of action of all repurposing drugs for effective multidrug-resistant TB (MDR-TB) management.

Many studies have been conducted globally for effective drug repurposing and immunotherapy for multidrug-resistant TB (MDR-TB) management. The success of immunotherapy in treating fatal diseases in the previous years has been in the limelight, and treating infectious diseases like TB with immunotherapeutic approaches holds great promise.

Conventional TB treatments face challenges like resistance and long durations. Immunotherapy and drug repurposing offer promising alternatives by enhancing immune response and using existing drugs with new applications. These strategies could improve outcomes in MDR-TB and warrant further clinical investigation.

In this review, we have summarised the immunomodulatory drugs that have been repurposed for tuberculosis treatment. Drug repurposing is a cost-effective and time-efficient method of developing new drugs by repurposing an existing drug for a new therapeutic use.

Haemophilus influenzae, a gram-negative, facultative anaerobic coccobacillus, is a member of the Pasteurellaceae family. It causes a variety of invasive and non-invasive bacterial infections known as H. influenzae infections. The increasing prevalence of antibiotic resistance highlights the need to identify novel therapeutic targets for treating H. influenzae infections. The emerging trends in the field of Pharmacoinformatics have aided in the prediction of novel putative therapeutic targets.

This study aims to identify novel putative therapeutic targets in H. influenzae using a subtractive genomic approach.

Subtractive Genomics, a simple yet powerful approach for the identification of novel therapeutic targets for bacterial pathogens, was employed in this study. The core proteome of 72 strains of H. influenzae was analysed through a multi-step filtration process to exclude the non-essential proteins and those homologous to the human proteome. Metabolic pathway analysis was conducted to identify pathogen-specific proteins, followed by druggability analysis and three-dimensional structure prediction.

On analysing the core proteome, 115 proteins were found to be unique and non-homologous to the human proteome. Further screening of these proteins led to the identification of 25 proteins involved in the 29 unique metabolic pathways of bacteria. Subsequent analysis finally resulted in the identification of five novel therapeutic targets for H. influenzae that are unique, non-homologous to the human proteome, essential for bacterial survival, and involved in unique metabolic pathways of bacteria.

This study successfully identified five novel therapeutic targets through subtractive genomics, contributing to the efforts against antimicrobial resistance in H. influenzae. Further experimental validation is necessary to strengthen these findings and advance therapeutic development.

To investigate the pharmacological implications of the ligand cis-4-Benzyl-2,6-diphenyltetrahydropyran, focusing on its pathways, potential disease associations, and therapeutic applications in Type 2 Diabetes Mellitus (T2DM).

Cis-4-Benzyl-2,6-diphenyltetrahydropyran has been previously identified for its heightened binding affinity to T2DM targets. Understanding its diverse pathways and interactions with neurotransmitter signaling, neuronal receptors, and enzymes/metabolism can provide insights into its potential roles in disease modulation and therapeutic applications.

The primary objective of this study was to investigate the pharmacological effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran in the context of Type 2 Diabetes Mellitus (T2DM). The study sought to understand its influence on neurotransmitter signaling, focusing on its modulation of G Protein-Coupled Receptors (GPCRs) and their role in diabetes pathogenesis. Utilizing KEGG pathway and gene ontology analyses, the study aimed to explore the ligand's involvement in neuroactive ligand-receptor interactions and the calcium signaling pathway, examining its broader impact on biological functions like inflammation, immune response, reproductive processes, and cellular metabolism associated with diabetes.

The study employed KEGG pathway and gene ontology analyses to profile cis-4-Benzyl-2,6-diphenyltetrahydropyran. The ligand's influence on neurotransmitter signaling, neuronal receptors, enzymes, and metabolic pathways was examined. Enrichment analysis was conducted to identify associated genes and pathways, focusing on the ligand's role in Neuroactive ligand-receptor interaction and the Calcium signaling pathway. Molecular docking and molecular dynamic simulations were performed to assess the ligand's interaction with the OPRK1 receptor, a G protein-coupled receptor implicated in metabolic regulation. Binding stability was analyzed using Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), and Solvent Accessible Surface Area (SASA). MMPBSA binding free energy analysis was conducted to validate the stability and strength of the ligand-receptor interaction.

The study revealed that cis-4-Benzyl-2,6-diphenyltetrahydropyran significantly impacts neurotransmitter signaling and cellular homeostasis by modulating GPCR pathways, including neuroactive ligand-receptor interaction and calcium signaling pathways. These pathways play critical roles in inflammation, immune response, reproductive processes, and cellular metabolism. Molecular docking and dynamic simulations demonstrated a strong and stable binding between the ligand and the OPRK1 receptor, a key GPCR implicated in metabolic regulation. The binding was supported by favorable binding free energy values (-255.58 kJ/mol) and consistent structural stability metrics, including minimal deviations in RMSD (0.2–0.4 nm) and stable radius of gyration (2.35–2.45 nm). Solvent Accessible Surface Area (SASA) analysis confirmed a compact ligand-receptor interaction, while hydrogen bonding reinforced binding specificity. These findings highlight the ligand's relevance in diabetes pathogenesis, particularly in regulating pathways involved in insulin sensitivity and glucose metabolism.

This study advances our understanding of the cellular effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran, highlighting its multifaceted potential in diabetes research. The strong interaction with OPRK1 suggests that the ligand could influence key pathways related to insulin sensitivity and metabolic regulation. However, the findings are derived from computational methodologies, and experimental validation through in vitro and in vivo studies is essential to confirm the ligand's biological activity and therapeutic relevance. The findings establish a foundation for targeted investigations and drug development, positioning this ligand as a promising candidate for therapeutic applications in diabetes mellitus.

The research highlights the effect of phytochemical compounds on the correlation of cellular pathways of cytokines and antioxidant enzymes at the molecular levels.

This work examines the effects of phytochemical substances on the expression of (IL1β and IL6, IL10) genes present in different amounts in garlic, grape seed, and pomegranate extracts in various amounts. Within the same framework, genes (SOD1, NFE2L2, JUN) expressing themselves genetically are responsible for the cellular pathways that carry out oxidative and redox reactions in cells.

Extracts of grape seeds (1.2% or 2.4%), pomegranates (1.2% or 2.4%), and garlic (0.5% or 1.2%) were applied to human peripheral blood leukocyte cultures. Real-time polymerase chain reaction (PCR) was utilised to evaluate the expression of genes.

We found that the level transcription of the SOD1 gene negatively correlates with the level transcription of cytokines IL1β when grape seed extract (2.4%) is added to the medium for culturing human blood cells. Furthermore, with the addition of 1.2% and 2.4% grape seed extract, there is a link between the expression of the SOD1 and IL6 genes. We found a positive correlation between the expression of the NFE2L2 and IL10 genes after adding pomegranate extract (1.2%). Finally, following the addition of grape seed extract (1.2%) and garlic extract (1.2%), there is a link observed between the transcription level of the JUN and IL1b genes.

The importance of the study lies in revealing the effect of phytochemicals on the intersection of the two pathways: the inflammatory pathway and the oxidative pathway. Whereas, it gives a clearer picture of the mechanism of action of these compounds as antioxidants and anti-inflammatories, depending on the close relationship between inflammatory properties and oxidative properties.

Lung cancer (LC) is a lethal malignancy with a late diagnosis and poor prognosis. During the last decade, the identification of oncogenic driver alterations has noticeably changed the therapeutic landscape and contributed to the emergence of the “oncogene addiction” concept and precision medicine in oncology. Among these alterations, the spotlight has turned to driver mutations in the KRAS and BRAF genes, which have garnered significant attention due to the emergence of targeted therapies and the potential for personalized treatment strategies.

Hence, the present study aimed to evaluate the mutational landscape of the KRAS and BRAF genes in LC Moroccan patients along with their frequencies and their correlation with clinicopathological features.

A total of 60 fresh biopsies were collected from patients with primary LC and were subjected to PCR-DNA sequencing of exon 2 of KRAS and exon 15 of BRAF genes in order to detect the most common mutations known by their implication in response to targeted therapies.

Sequencing analysis revealed that mutations in KRAS and BRAF genes represented respectively 8.3% and 6.7% of cases; one patient had two KRAS mutations (G12A and K5E), and none had simultaneous BRAF and KRAS mutations. The vast majority of patients harboring KRAS mutations were men, formal smokers with adenocarcinomas, and at advanced stage (stage III). BRAF mutations were mainly detected in men and non-smokers with adenocarcinoma. Statistical analyses showed no significant correlation between KRAS and BRAF substitutions and clinico-pathological features (p>0.05).

The presence of these mutations will be used as a valuable molecular biomarker to select potential candidates eligible for effective personalized therapy using available agents targeting these mutations. However, much effort is needed to identify other druggable mutations to generalize personalized LC therapy for better management of this devastating disease.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of benign tumors due to mutations in the NF1 gene, which encodes the tumor suppressor neurofibromin. This study aimed to identify novel inhibitors of neurofibromin through drug repurposing of clinical trial compounds from the Zinc15 database.

Utilizing advanced in silico techniques, we conducted molecular docking via PyRx and molecular dynamics simulations with GROMACS. Among the compounds analyzed, ZINC000261527152 (Tetrodotoxin) emerged as a promising candidate due to its binding affinity to NF1. Tetrodotoxin formed stable conventional and carbon-hydrogen bonds with key residues, including GLU 981, GLY 984, GLN 985, SER 1030, SER 1561, and ASN 1563. Molecular dynamics simulations confirmed the stability of the Tetrodotoxin-NF1 complex, with favorable RMSD, RMSF, radius of gyration (Rg), and solvent-accessible surface area (SASA) values over a 100 ns simulation period.

These results suggest that Tetrodotoxin could effectively inhibit neurofibromin, presenting a novel therapeutic approach for neurofibromatosis. However, despite the promising computational findings, further experimental validation through in vitro and in vivo studies is essential to confirm the efficacy and safety of Tetrodotoxin as a treatment for NF1.

This research underscores the utility of computational drug repurposing methodologies and their role in accelerating the discovery of novel treatments for genetic disorders, particularly neurofibromatosis, thereby potentially improving patient outcomes and quality of life.

The Calcitonin receptor (CALCR) gene encodes a protein essential for bone metabolism, playing a key role in inhibiting bone resorption and promoting renal calcium excretion. Polymorphisms in CALCR have been associated with differences in bone mineral density, osteoporosis, and an increased risk of calcium stone urolithiasis.

This study aimed to investigate the non-synonymous SNPs of human genes.

This study was conducted to analyse the structural and functional impact of high-risk non-synonymous single nucleotide polymorphisms (nsSNPs) in the CALCR gene using bioinformatics tools.

We retrieved nsSNPs from the NCBI and Uniprot databases and assessed their deleterious potential using SIFT, PolyPhen v2, PROVEAN, PANTHER, PhD-SNP, and SNPs and GO. Gene-gene interactions were examined with GeneMANIA, while protein-protein interactions were analyzed via STRING. Structural and functional predictions were performed using I-Mutant, MUPro, ConSurf, SOPMA, NetSurf 2.0, AlphaFold, and NetPhos 3.1.

Our analysis found 17 deleterious nsSNPs (rs972946, rs138829125, rs146344939, rs148707949, rs149570603, rs149628324, rs200643258, rs200900623, rs201985045, rs267601640, rs368981699, rs369253212, rs369926913, rs371453754, rs374929068, rs375143115, rs375417465) that destabilize the CALCR protein. ConSurf revealed that 9 of these high-risk nsSNPs are located in conserved regions, with the variants S129Y, R321Q, D101Y, D77V, L176F, P122S, N312S, M187T, and W406R being identified as highly conserved. NetsurfP-2.0 analysis indicated that some nsSNPs are exposed while others are buried, and phosphorylation analysis highlighted variations in threonine and tyrosine residues.

These findings indicate that the identified nsSNPs may substantially affect the functionality of CALCR and could potentially be used as biomarkers for disease diagnosis and targets for therapy.

Dental caries is a biofilm-mediated disease driven by dietary sugars that reduce pH and promote cariogenic microorganisms. Caries result from a complex interplay of behaviour, environmental, genetic, and physiological factors, with the immune response and bacterial activity contributing to enamel demineralization and cavity formation. Genetic factors, such as SNPs, also influence caries susceptibility, impacting enamel hardness and inflammatory responses.

This study aims to explore the association between the ALOX12 gene variant, rs9904779, and the susceptibility to dental caries.

Patients were recruited following ethical approval and informed consent. Saliva samples were collected and grouped by DMFT index, and genomic DNA was extracted. PCR analysis focused on ALOX12 gene polymorphism with the 223 bp product and RFLP. Statistical analysis was performed using Epi Info software, calculating genotype-risk associations and a significance threshold of p < 0.05. Chi-square testing assessed genotype and allele distributions across groups.

An SNP analysis of ALOX12 was conducted to assess the susceptibility of dental caries. In caries patients, CC genotype was most prevalent (42%), while CG was higher in controls (52%). Genotype distribution deviated from Hardy-Weinberg equilibrium in caries (p < 0.05) but not in controls (p > 0.05). The caries group had a higher prevalence of the C allele, while the CG heterozygote was more frequent in controls (OR = 0.64, p = 0.32).

This SNP analysis suggests that the ALOX12 gene variant rs9904779 may be a significant predictor for the development of dental caries, highlighting its potential as a genetic marker for susceptibility to the disease.

To examine whether novel lead hypertension molecules can be used in the personalized treatment of hypertension.

Hypertension is a modifiable condition that affects over 1 billion adults worldwide. Maintaining a healthy blood pressure is vital for overall health, especially given that hypertension is a primary risk factor for developing cardiovascular conditions. However, some individuals have resistant hypertension, which may be due to variations in genetic expression, making standard hypertension treatments ineffective.

The integration of genetic data into the personalized optimization of novel hypertension drugs is demonstrated.

This research created coding criteria for drug-gene recommendations based on the genomic profiles of ten pseudo-patients. The genomic data of these patients was created using chromosome and hypertension-implicated gene sequences from the NCBI National Library of Medicine database.

This study uses the proposed drug recommendation criteria to recommend novel hypertension lead molecules to each patient based on their gene expression profiles.

This study’s patient-centric drug prescription approach integrates patient gene expression data with drug-gene interaction data and recommends novel hypertension drugs most suitable for each patient. Variations in patient gene expression explain the diverse treatment responses inherent across hypertensive patients, thus necessitating a personalized approach to their drug prescription. Future studies can investigate the challenges of ethical, technological, and technical expertise that may affect the clinical implementation of personalized drug prescription recommendation systems.

Dental caries result from the demineralization of enamel or dentin caused by acids produced by cariogenic oral bacteria. The Glutathione S-transferase P1 (GSTP1) is a prominent member of the GST family, and it exhibits several genetic polymorphisms, with rs1695 being the most common variant.

Our study is to investigate the relationship between GSTP1 rs1695 polymorphism and the susceptibility to dental caries.

The study focused on understanding the relationship between GSTP1 rs1695 polymorphisms and susceptibility to dental caries in the Tamil population.

SNPs in the GSTP1 missense variant rs1695 (A/G) were analysed by PCR RFLP. The study group included 100 dental caries with (DMFT >5) and 100 healthy controls (DMFT=0). Further analysis of the impact of the GSTP1 wild-type gene with the rs1695 variant on mRNA's secondary structure was conducted using in silico prediction tools.

The results showed a significant frequency distribution of the heterozygous AG genotype (p<0.05). While the genotypic distribution of GSTP1 remained consistent with Hardy-Weinberg equilibrium (HWE) in the control group (p-value > 0.05), it deviated from HWE in the caries group. The free energy of the thermodynamic ensemble for the rs1695 variant was calculated to be -186.20 kcal/mol. This lower free energy, compared to the wild-type, indicates that the variant is more stable.

Our findings indicate that GSTP1 rs1695 variants could enhance susceptibility to dental caries by suggesting genetic load as a possible risk factor. However, additional functional research and larger studies are required to confirm these results.

Cancer is one of the serious health issues and the leading cause of mortality worldwide. Several studies have demonstrated that the overexpression of growth factors and receptors, the triggering of oncogenes, and the deactivation of tumor suppressor genes are the main causes of aggressive and resistant forms of cancer. The epidermal growth factor receptor (EGFR) is a receptor that medications target for cancer treatment.

The present study employs computational approaches to explore the anti-cancer activity of newly identified indole alkaloids from Zanthoxylum nitidum against EGFR kinase.

Computational techniques, including molecular docking, density functional theory (DFT), and in-silico pharmacokinetic studies, were employed to evaluate the ligand-target interactions. Additionally, drug-likeness was assessed using the Lipinski rule of five.

We evaluated their pharmacokinetics, binding interactions, and stability using molecular docking, drug-likeness prediction, absorption, distribution, metabolism, and excretion (ADMET) profiling, simulations study, and density functional theory (DFT) study. Nitidumalkaloid C showed remarkable binding affinity (-9.7 kcal/mol) to epidermal growth factor receptor tyrosine kinase, while that of standard drugs showed dacomitinib (-9.0 kcal/mol) and osimertinib (-7.9 kcal/mol). The molecular dynamics MD simulation study revealed stable interactions, with nitidumalkaloid C exhibiting the highest stability. These findings indicate indole alkaloids as potentially effective anticancer medicines, with nitidumalkaloid C demanding further modification for pharmaceutical development. This research informs nitidumalkaloid C as a potential indole alkaloid by providing insights into molecular characteristics and binding energies.

These parameters allow consideration of the most promising candidate, nitidumalkaloid C, for novel anticancer drug development to overcome gene mutations or resistance in EGFR-TK.