Su Datt Lam

Background: Thymol, a natural phenol with antimicrobial and antioxidant activities, and its derivatives offer promising scaffolds for antimalarial drug development, potentially helping overcome resistance. Materials and Methods: In this study, thymol derivatives were synthesized and assessed as antiplasmodial agents against both resistant and sensitive strains of P. falciparum, as well as Plasmodium knowlesi. The ligand molecules were assessed with Plasmodium falciparum chloroquine resistance transporter (PfCRT)’s potential using in silico molecular docking and ADMET analysis. The parent compound, thymol, was chemically modified through esterification and conjugation with hydroxybenzoic acid and cinnamic acid derivatives to generate analogs with varied substitution patterns. Results: The findings showed that among seven successfully synthesized thymol derivatives, compounds 4 and 6 exhibited notable potency against Plasmodium falciparum 3D7 (EC₅₀ = 6.01 ± 1.7 µM and 6.8 ± 1.1 µM, respectively) with high SI values (16.5 and 14.6, respectively), indicating improved selectivity relative to thymol. The cytotoxicity evaluation against HCF mammalian cells revealed that most thymol derivatives were non-toxic, with CC₅₀ values greater than 99 µM, except for compound 3 (CC₅₀ = 71.4 ± 4.5 µM) and compound 1 (CC₅₀ = 58.4 ± 2.3 µM), which exhibited moderate cytotoxic effects. The molecular docking results showed that compounds 3 (−8.4 kcal/mol), 4 (−8.3 kcal/mol), and 6 (−8.3 kcal/mol) exhibited strong binding affinities toward the PfCRT protein. Conclusions: Therefore, thymol derivative compounds 4 and 6 exhibited stronger antiplasmodial activity in vitro against P. falciparum and P. knowlesi with safety profiles against mammalian cells, targeting PfCRT, highlighting their potential as lead antimalarial candidates.

Motivation: Plants have evolved adaptive mechanisms to handle environmental stress. However, genome-wide association studies (GWASs) have identified genetic variations associated with stress resistance, yet their structural and functional impacts remain poorly understood. This limits our ability to develop more resilient crops. Results: Using predicted three-dimensional protein structures from the AlphaFold Database, chopped into domains by The Encyclopedia of Domains, we analysed how mutations identified in rice GWASs affect protein structure and function. The analysis revealed 102 mutations in 76 high-quality protein domains likely to impact structure and function. Thirty-nine mutations were positioned within 5 Å of predicted functional sites, including those near post-translational modification sites (3), allosteric sites (5), protein–protein interaction sites (25), ligand-binding sites (15), and conserved regions (9). We identified potential interaction partners for 18 proteins with mutations at predicted interfaces and modelled their complex structures. Six mutations were predicted to enhance binding affinity with their protein partners. Availability and implementation: This study utilized only open-access tools and and provides a framework that could strengthen plant defence mechanisms. However, experimental validation is essential to confirm the applicability of these findings for plant breeding programs.

Burkholderia pseudomallei (BP) infections claims tens of thousands of lives worldwide every year. The bacterium's distinctive characteristics include antibiotic resistance, virulence and ability to survive in stressful environments. The B. pseudomallei genome sequencing and annotation reveal that about 25% of the genes encode hypothetical proteins (HPs). As such, characterising the HPs could shed light on the mechanisms that contribute to the above characteristics. Over the last decade, genome sequencing and annotation technologies have advanced drastically. Furthermore, artificial intelligence programs such as AlphaFold2 (AF2), RoseTTAFold2 (RF2), which can predict 3D protein structures with high accuracy, are also available. Taking advantage of the available tools, this study aimed to re-annotate HPs that are encoded within the BP genome. To achieve this, we retrieved 1869 HPs from the Burkholderia Genome Database, then cross-referenced with UniProt. After filtering, 419 remain hypothetical. These were analysed using BLASTp for sequence homologs and antibiotic resistance proteins, followed by 3D structure prediction using AF2 and RF2, and structural homolog search using Foldseek. This study successfully annotated 209 HPs with only 210 proteins (3.7% of BP coding sequences) still classified as ‘hypothetical’. The functions of the predicted HPs were further analysed using structure comparison and active site analysis. The annotated protein list includes fifteen antibiotic resistance proteins, five haem oxygenase-like fold proteins involved in biofilm formation, host pathogenesis, and antibacterial activity, along with five essential proteins. These proteins represent promising drug targets for developing new antibiotics against melioidosis. Nonetheless, experimental validation will be necessary to characterize the predicted protein functions. Graphical Abstract

Epilepsy is a neurological disorder affecting millions of people worldwide. Antiseizure medications (ASM) remain a critical therapeutic intervention for treating epilepsy, notwithstanding the rapid development of other therapies. There have been substantial advances in epilepsy medications over the past three decades, with over 20 ASMs now available commercially. Here we describe the conventional and unique mechanisms of action of ASMs, focusing on everolimus, cannabidiol, cenobamate, fenfluramine, and ganaxolone, the five most recently marketed ASMs. Major obstacles in the development of ASMs are also addressed, particularly drug-resistant epilepsy as well as psychiatric and behavioral adverse effects of ASMs. Moreover, we delve into the mechanisms and comparative efficacy of ASM polytherapy, with remarks on the benefits and challenges in their application in clinical practice. In addition, the characteristics of the ideal ASM are outlined in this review. The review also discusses the development of new potential ASMs, including modifying existing ASMs to improve efficacy and tolerability. Furthermore, we expound on the modulation of γ- aminobutyric acid type A receptor (GABAAR) as a strategy for the treatment of epilepsy and the identification of a GABAAR agonist, isoguvacine, as a potential ASM.

Glycochemistry has broadened the scope of drug discovery by offering new avenues for developing potent and safe medicines. Glycosylation improves physicochemical and pharmacokinetic properties of bioactive compounds, inspiring further exploration of glycosylated drug candidates. This review delves into the significance of carbohydrate-based bioactive compounds with promising antiplasmodial and antimalarial activity for the development of effective antimalarials.

Plants face formidable challenges due to environmental stresses, including pathogens, salt, drought, cold, heat, heavy metal exposure, and flooding, all of which affect growth and agricultural productivity. To combat these stresses, plants have evolved various adaptive mechanisms, including the expression of stress-response proteins. Exploring the three-dimensional structures of plant proteins can be valuable for discovering and characterising stress tolerance mechanisms at the molecular level. Until recently, large-scale analyses were not feasible due to the limited number of experimentally determined plant protein structures. However, the recently developed AlphaFold, RoseTTA-Fold, and ESM-fold protein structure prediction methods, along with their associated portals, now provide hundreds of millions of high-quality predicted 3D models, covering a wide range of plant proteins. This review highlights insights from recent structural investigations into plant stress response using experimental or predicted protein structures. We include analyses of diverse paralogs and isoforms and insights from molecular docking and molecular dynamics simulations. We consider the value of using experimental and predicted structural data in understanding the mechanisms of common stress-modulating plant proteins. Studying the structures of these proteins together with their inferred functions can aid improvements in crop productivity, help foster sustainable agriculture, and contribute to global food security efforts.

The four papers in this special section were presented at the 20th Asia Pacific Bioinformatics Conference (APBC), which was held in Malaysia 26-28 April 2022.

Adenosine triphosphate (ATP)-binding cassette (ABC) transporter systems are divided into importers and exporters that facilitate the movement of diverse su

Antimicrobial resistance (AMR) poses a significant threat to global public health, with the potential to cause millions of deaths annually by 2050. Effective surveillance of AMR pathogens is crucial for monitoring and predicting their behaviour in response to antibiotics. However, many public health professionals lack the necessary bioinformatics skills and resources to analyse pathogen genomes effectively. To address this challenge, we developed AMRColab, an open-access bioinformatics analysis suite hosted on Google Colaboratory. AMRColab enables users with limited or no bioinformatics training to detect and visualize AMR determinants in pathogen genomes using a ‘plug-and-play’ approach. The platform integrates established bioinformatics tools such as AMRFinderPlus and hAMRonization, allowing users to analyse, compare and visualize trends in AMR pathogens easily. A trial run using methicillin-resistant Staphylococcus aureus (MRSA) strains demonstrated AMRColab’s effectiveness in identifying AMR determinants and facilitating comparative analysis across strains. A workshop was conducted and feedback from participants indicated high confidence in using AMRColab and a willingness to incorporate it into their research. AMRColab’s user-friendly interface and modular design make it accessible to a diverse audience, including medical laboratory technologists, medical doctors and public health scientists, regardless of their bioinformatics expertise. Future improvements to AMRColab will include enhanced visualization tools, multilingual support and the establishment of an online community platform. AMRColab represents a significant step towards democratizing AMR surveillance and empowering public health professionals to combat AMR effectively.