Similar Binding Sites Research Articles

Novel Modified Piperacillin Inhibitors of Penicillin-Binding Protein 3 (PBP3) and Their Intermolecular Interactions.

<b>Background and Objective:</b> Despite the rise of antibiotic resistance, penicillin and the broader group of β-lactams have continued to be the most crucial class of antibiotics. Penicillin-Binding Protein 3 (PBP3) in <i>Pseudomonas aeruginosa</i> is the specific molecule that β-lactam-based medicines target. The objective is to design and study several piperacillin derivatives to create novel antibacterial agents. <b>Materials and Methods:</b> Piperacillin derivatives were drawn using chem sketch and prepared using AutoDock 4.2.6 Tools. Molecular docking simulations were conducted on novel piperacillin derivatives and piperacillin (Control) against the 6r3x.PDB protein. The AutoDock log files were analyzed to determine the lowest energy of binding (LEB) values for each ligand. Consequently, the conformer with the most favorable binding energy may be identified. <b>Results:</b> All of the proposed piperacillin derivatives displayed improved binding energies when compared to the reference chemical piperacillin. This suggests the potential for stronger interactions between derivatives and proteins, resulting in an enhanced likelihood of biological effects. Compounds b, e and j, when used alongside piperacillin, showed similar binding sites inside the active site and have the potential for additional characterization. <b>Conclusion:</b> Compounds b, e and j are highly likely to exhibit inhibitory activity, indicating that they should be synthesized and tested for biological activity.

Root Zn sequestration transporter heavy metal ATPase 3 from Odontarrhena chalcidica enhance Cd tolerance and accumulation in Arabidopsis thaliana

The Ni hyperaccumulator Odontarrhena chalcidica (formerly Alyssum murale), exhibits a significant capacity to accumulate Zn in the roots. However, the molecular mechanisms underlying the variation in Ni and Zn accumulation are poorly understood. Here, we isolated a homolog of heavy metal ATPase 3 from O. chalcidica (OcHMA3) and characterized its functions using heterologous systems. Phylogenetic analysis revealed that OcHMA3 protein shares 87.6 % identity with AtHMA3, with similar metal binding sites to other HMA3 proteins. Heterologous expression of OcHMA3 in yeast increased sensitivity to Cd, Ni and Zn, suggesting it functions as a broad-specificity transporter. Further investigation showed OcHMA3 is constitutively expressed in the roots and localized to the tonoplast. Overexpression of OcHMA3 in A. thaliana shoots increased its roots Zn concentrations by 41.9 % – 74.1 %. However, overexpression of OcHMA3 in roots enhanced its tolerance to Cd and increased roots Cd concentrations by 50.9 % – 90.6 %. Our findings indicated OcHMA3 is responsible for Zn sequestration in root vacuoles, likely leading to Zn retention in roots and subsequent Ni hyperaccumulation in shoots. This study elucidates the molecular mechanism of Ni and Zn accumulation in O. chalcidica, and identifies OcHMA3 as a potential gene for developing Zn-rich plants and for phytoextraction in Cd-contaminated soils.

Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L

The mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2) is involved in purine and thymidine synthesis via 1C metabolism. MTHFD2 is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. However, the two close homologs of MTHFD2 known as MTHFD1 and MTHFD2L are expressed in healthy adult human tissues and share a great structural resemblance to MTHFD2 with 54% and 89% sequence similarity, respectively. It is therefore notably challenging to find selective inhibitors of MTHFD2 due to the structural similarity, in particular protein binding site similarity with MTHFD1 and MTHFD2L. Tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported till date. Nanomolar potent diaminopyrimidine-based inhibitors of MTHFD2 have been reported recently, however, they also demonstrate significant inhibitory activities against MTHFD1 and MTHFD2L. In this study, we have employed extensive computational modeling involving molecular docking and molecular dynamics simulations in order to investigate the binding modes and key interactions of diaminopyrimidine-based inhibitors at the substrate binding sites of MTHFD1, MTHFD2 and MTHFD2L, and compare with the tricyclic coumarin-based selective MTHFD2 inhibitor. The outcomes of our study provide significant insights into desirable and undesirable structural elements for rational structure-based design of new and selective inhibitors of MTHFD2 against cancer.

In silico evidence of bitopertin's broad interactions within the SLC6 transporter family.

The Glycine Transporter Type 1 (GlyT1) significantly impacts central nervous system functions, influencing glycinergic and glutamatergic neurotransmission. Bitopertin, the first GlyT1 inhibitor in clinical trials, was developed for schizophrenia treatment but showed limited efficacy. Despite this, bitopertin's repositioning could advance treating various pathologies. This study aims to understand bitopertin's mechanism of action using computational methods, exploring off-target effects, and providing a comprehensive pharmacological profile. Similarity Ensemble Approach (SEA) and SwissTargetPrediction initially predicted targets, followed by molecular modeling on SWISS-MODEL and GalaxyWeb servers. Binding sites were identified using PrankWeb, and molecular docking was performed with DockThor and GOLD software. Molecular dynamics analyses were conducted on the Visual Dynamics platform. Reverse screening on SEA and SwissTargetPrediction identified GlyT1 (SLC6A9), GlyT2 (SLC6A5), PROT (SLC6A7), and DAT (SLC6A3) as potential bitopertin targets. Homology modeling on SwissModel generated high-resolution models, optimized further on GalaxyWeb. PrankWeb identified similar binding sites in GlyT1, GlyT2, PROT, and DAT, indicating potential interaction. Docking studies suggested bitopertin's interaction with GlyT1 and proximity to GlyT2 and PROT. Molecular dynamics confirmed docking results, highlighting bitopertin's target stability beyond GlyT1. The study concludes that bitopertin potentially interacts with multiple SLC6 family targets, indicating a broader pharmacological property.

Sulfate-reducing consortium HQ23 stabilizes metal(loid)s and activates biological N-fixation in mixed heavy metal-contaminated soil

Sulfate-reducing bacteria (SRB) are used in the remediation of mine pollution; however, the mechanism of stabilizing multiple heavy metal(loid)s by the SRB consortium under low oxygen conditions needs further study. Indigenous microflora were extracted from non-ferrous metal-contaminated soil co-inoculated with enriched SRB consortium and assembled as the HQ23 consortium. The presence of Desulfovibrio (SRB) in HQ23 was confirmed by 16S rRNA sequencing and qPCR. The effects of culture media, dissolved oxygen (DO), SO42¯, and pH on the HQ23 growth rate, and the SO42¯-reducing activity were examined. Data indicates that the HQ23 sustained SRB function under low DO conditions (3.67 ± 0.1 mg/L), but the SRB activity was inhibited at high DO content (5.75 ± 0.39 mg/L). The HQ23 can grow from pH 5 to pH 9 and can decrease mobile or bioavailable Cr, Cu, and Zn concentrations in contaminated soil samples. FTIR revealed that Cu and Cr adsorbed to similar binding sites on bacteria, likely decreasing bacterial Cu toxicity. Increased abundances of DSV (marker for Desulfovibrio) and nifH (N-fixation) genes were observed, as well as an accumulation of nitrate-N content in soils suggesting that HQ23 stimulates the biological N-fixation in soils. This study strongly supports the future application of SRB for the bioremediation of heavy metal-polluted sites.

Mechanism of the blood-brain barrier modulation by cadherin peptides.

This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB). ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) 1H-15N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy. Molecular docking experiments were used to determine the binding sites of these peptides to the EC1 domain of E-cadherin. This study indicates that ADTC5 has the highest binding affinity to the EC1 domain of E-cadherin compared to ADTC7 and ADTC9, suggesting the importance of the Val6 residue as shown in our previous in vitro study. All three peptides have a similar binding site at the hydrophobic binding pocket where the domain swapping occurs. ADTC5 has a higher overlapping binding site with ADTC7 than that of ADTC9. Binding of ADTC5 on the EC1 domain influences the conformation of the EC1 C-terminal tail. These peptides bind the domain swapping region of the EC1 domain to inhibit the trans-cadherin interaction that creates intercellular junction modulation to increase the BBB paracellular porosity.

Abstract A002: Understanding mechanisms of resistance to WRN small molecule inhibitors

Abstract The Werner syndrome helicase (WRN) has emerged as a promising synthetic lethal target in cancers with microsatellite instability (MSI). This discovery has spurred numerous efforts developing therapeutics targeting WRN and the advancement of at least two WRN programs into Phase I clinical trials. The development of acquired resistance remains a significant obstacle for the durable efficacy of targeted therapies in oncology and this challenge may be particularly pronounced in the setting of mismatch repair deficient (dMMR) tumors, which inherently possess large reservoirs of mutational burden. Despite the potential of WRN-targeted treatments, there remains a notable gap in the literature concerning the mechanisms of resistance to these drugs. To explore potential acquired resistance mechanisms of WRN-directed therapies, we examined three helicase inhibitors—HRO761 and two proprietary compounds which all possess a similar mechanism of action (MOA). Continuous treatment of HCT116 and SW48 cell lines with these inhibitors rapidly lead to the emergence of phenotypically resistant cell populations. Subsequent sequencing of several independently derived resistant cultures identified 5 emergent point mutations within the helicase domain of WRN that are potentially responsible for the observed inhibitor resistance. Parallel in vivo studies with HRO761 in SW48 xenograft tumors also demonstrated the acquisition of resistance after an initial period of deep response. Whole exome sequencing of these tumors revealed 2 of the previously observed, as well as 4 novel WRN helicase mutations. Structural modeling of WRN with putative resistance mutations suggested their capacity to either directly impede inhibitor binding or disfavor the adoption of the compound binding confirmation. Surprisingly, despite the general similarity in MOA and ligand binding sites, cross-resistance analyses demonstrated that some mutations conferred preferential resistance to HRO761 and were only minimally detrimental to the activity of our proprietary compounds. We conclude that WRN inhibitor monotherapy leads to drug resistance by acquisition of on-target mutations that disrupt inhibitor binding through direct or indirect mechanisms. This process may be extremely rapid in the dMMR background that represents the intent to treat population for WRN-directed therapeutics and is potentially further exacerbated by the complex allosteric MOA of WRN inhibitors currently in the clinic. Notably, some WRN inhibitor-resistant cell lines were not resistant to all WRN inhibitors tested, suggesting the potential for employing different WRN inhibitors at different stages of treatment to overcome resistance. This study underscores the importance of understanding and addressing resistance mechanisms to enhance the effectiveness of WRN-targeted therapies in MSI cancers. Citation Format: Faith C. Fowler, Aileen Kelly, Cindy Jeffries, Jessica Gajda, Jonathan Hickson, Fei Han, Nate Elsen, Mariam George, Danli Towne, Xiangdong Xu, Nate Gesmundo, Wei Qiu, Henry Tang, Charlie Hutchins, Yunsong Tong, Mick Dart, Ari Firestone. Understanding mechanisms of resistance to WRN small molecule inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A002.

Investigating emodin derivatives against SARS-CoV-2 found in medicinal herbs

SARS-CoV-2 continues to mutate and circulate at alarming levels around the world and is exemplified by the emergence of the new variant JN.1. The emergence of novel SARS-CoV variants underscores the urgency for the development of new drugs. Phytochemicals, known for their safety and efficacy, have been widely used to address various ailments. This study aims at identifying the anti-SARS-CoV potential of emodin, a bioactive anthraquinone, and its derivatives. Key proteins, including hemagglutinin-esterase (HE), papain-like protease (PLpro), major protease (3CLpro), non-structural protein (nsp3) and spike protein(S) of SARS-CoV, were used as protein targets for the virtual screening of 110 emodin derivatives (ED) and remdesivir a proven antiviral drug. Among the 110 derivatives, ED21, ED25, ED5 inhibited HE, 3CLpro and S protein, respectively. ED29 inhibited both PLpro and nsp3 with high binding affinity. Similar receptor binding sites were occupied by remdesivir and emodin derivatives. These emodin derivatives are bound to similar amino acids in receptors as compared to remdesivir. Further dynamic simulations studies with ED21-HE, ED25-3CLpro, ED5-S, ED29-PLpro and ED29-nsp3 complexes showed all of them are stable with minimum root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent-accessible surface area (SASA) and radius of gyration (Rg) and are comparable to APO protein. All the ligands accepted Lipinski's rule of five. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed only ED21 and ED5 as promising druglike candidates that can have high therapeutic value and no side effects. These in-silico findings contribute to the development of potent SARS-CoV-2 inhibitors, potentially advancing the quest for effective antiviral drugs.

Genomic analysis of Salmonella bacteriophages revealed multiple endolysin ORFs and importance of ligand binding site of receptor binding protein.

Salmonella is a prevalent foodborne pathogen causing millions of global cases annually. Antimicrobial resistance is a growing public health concern, leading to search for alternatives like bacteriophages. 97 bacteriophages, isolated from cattle farms (n= 48), poultry farms (n=37), and wastewater (n=5) samples in Türkiye, were subjected to host range analysis using 36 Salmonella isolates with 18 different serotypes. The broadest host range belonged to an Infantis phage (MET P1-091), lysing 28 hosts. Ten phages with the widest host range underwent further analysis, revealing 7 unique genomes (32 to 243kb), including a jumbophage (>200kb). Except for one with lysogenic properties, none of them harbored virulence or antibiotic resistance genes, making them potential Salmonella reducers in different environments. Examining ORFs of endolysin enzymes revealed surprising findings: 5 of 7 unique genomes contained multiple endolysin ORFs. Despite sharing same endolysin sequences, phages exhibited significant differences in host range. Detailed analysis unveiled diverse receptor binding protein sequences, with similar structures but distinct ligand binding sites. These findings emphasize the importance of ligand binding sites of receptor binding proteins. Additionally, bacterial reduction curve and virulence index revealed that Enteritidis phages inhibit bacterial growth even at low concentrations, unlike Infantis and Kentucky phages.

Systemic Anti-inflammatory Activity of American Cockroach (Periplaneta americana) Extract: A Molecular Docking Study

Surgery can trigger systemic inflammatory response syndrome. This study aims to determine the effectiveness of Periplaneta americana cockroach extract as an oral systemic anti-inflammatory agent using molecular docking. The molecular docking method consisted of five steps. The first step was preparing the TNF-α converting enzyme (TACE) receptor as a native ligand, dexamethasone as a control ligand, and three test ligands of Periplaneta americana cockroach extract. The second step was docking preparation. The third step was analyzing Gibbs free energy (∆G) and root mean square deviation (RMSD). The fourth step was docking the test and control ligands with TACE. The fifth step was analyzing ∆G, inhibition constant (Ki), visualization of two- and three-dimensional interactions, percentage of binding site similarity (%BSS), and the rule of five (Ro5) on test ligands. The ∆G results for the native, control, and test ligands 1, 2, and 3 were -12.8, -7.1, -7.7, -6.9, and -9.0 kcal/mol, respectively. The Ki values for the native, control, and test ligands 1, 2, and 3 were 4.091, 6.205, 2.253, 9.521, and 2.507 µM, respectively. The results of the Ro5 analysis suggested that the three test ligands satisfied Lipinski’s rule of five. This study concluded that Periplaneta americana cockroach extract is an effective oral systemic anti-inflammatory agent.

Extensive Loss and Gain of Conserved Noncoding Elements During Early Teleost Evolution.

Conserved noncoding elements in vertebrates are enriched around transcription factor loci associated with development. However, loss and rapid divergence of conserved noncoding elements has been reported in teleost fish, albeit taking only few genomes into consideration. Taking advantage of the recent increase in high-quality teleost genomes, we focus on studying the evolution of teleost conserved noncoding elements, carrying out targeted genomic alignments and comparisons within the teleost phylogeny to detect conserved noncoding elements and reconstruct the ancestral teleost conserved noncoding elements repertoire. This teleost-centric approach confirms previous observations of extensive vertebrate conserved noncoding elements loss early in teleost evolution, but also reveals massive conserved noncoding elements gain in the teleost stem-group over 300 million years ago. Using synteny-based association to link conserved noncoding elements to their putatively regulated target genes, we show the most teleost gained conserved noncoding elements are found in the vicinity of orthologous loci involved in transcriptional regulation and embryonic development that are also associated with conserved noncoding elements in other vertebrates. Moreover, teleost and vertebrate conserved noncoding elements share a highly similar motif and transcription factor binding site vocabulary. We suggest that early teleost conserved noncoding element gains reflect a restructuring of the ancestral conserved noncoding element repertoire through both extreme divergence and de novo emergence. Finally, we support newly identified pan-teleost conserved noncoding elements have potential for accurate resolution of teleost phylogenetic placements in par with coding sequences, unlike ancestral only elements shared with spotted gar. This work provides new insight into conserved noncoding element evolution with great value for follow-up work on phylogenomics, comparative genomics, and the study of gene regulation evolution in teleosts.

VirtuousPocketome: a computational tool for screening protein–ligand complexes to identify similar binding sites

Protein residues within binding pockets play a critical role in determining the range of ligands that can interact with a protein, influencing its structure and function. Identifying structural similarities in proteins offers valuable insights into their function and activation mechanisms, aiding in predicting protein–ligand interactions, anticipating off-target effects, and facilitating the development of therapeutic agents. Numerous computational methods assessing global or local similarity in protein cavities have emerged, but their utilization is impeded by complexity, impractical automation for amino acid pattern searches, and an inability to evaluate the dynamics of scrutinized protein–ligand systems. Here, we present a general, automatic and unbiased computational pipeline, named VirtuousPocketome, aimed at screening huge databases of proteins for similar binding pockets starting from an interested protein–ligand complex. We demonstrate the pipeline's potential by exploring a recently-solved human bitter taste receptor, i.e. the TAS2R46, complexed with strychnine. We pinpointed 145 proteins sharing similar binding sites compared to the analysed bitter taste receptor and the enrichment analysis highlighted the related biological processes, molecular functions and cellular components. This work represents the foundation for future studies aimed at understanding the effective role of tastants outside the gustatory system: this could pave the way towards the rationalization of the diet as a supplement to standard pharmacological treatments and the design of novel tastants-inspired compounds to target other proteins involved in specific diseases or disorders. The proposed pipeline is publicly accessible, can be applied to any protein–ligand complex, and could be expanded to screen any database of protein structures.

Potential of Active Compounds in Broadleaf Mahogany (Swietenia macrophylla) Seeds Against Breast Cancer Cells Based on In Silico Study

Breast cancer is a leading cause of cancer-related deaths in Indonesia. However, the drugs that are commonly used for treatment can cause side effects and become resistant over time. A study was conducted to test the cytotoxic activity of broadleaf mahogany (Swietenia macrophylla) seed extract on MCF-7 breast cancer cells in vitro. The study aimed to predict active compounds in the broadleaf mahogany seeds that have the potential to act as anti-breast cancer agents using in silico analysis. Molecular docking, visualization of the interaction between the receptor and the ligands, and physicochemical analysis were used to determine the most promising compounds. The receptors used were fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), insulin-like growth factor type 1 receptor (IGF-1R), estrogen receptor (ER-α), and progesterone receptor (PR). The results showed that 12 compounds have the potential to be active as anti-breast cancer agents. Three of these compounds, 3β,6-dihydroxydihydrocarapine, stigmasterol, and 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chroman-4-one, were predicted to have similar mechanisms of inhibition as a comparator drug based on binding site similarity values. These compounds are predicted to be taken orally and are promising for further research.

Combinatorial preparation and structural characterization of anthocyanins and aglycones from Purple-heart Radish for evaluation of physicochemical stability and pancreatic lipase inhibitory activity

In this study, an efficient approach to preparation of different anthocyanins from Purple-heart Radish was developed by combining microwave-assisted extraction (MAE), macroporous resin purification (MRP) and ultrasound-assisted acid hydrolysis (UAAH) for evaluation of physicochemical stability and pancreatic lipase (PL) inhibitory activity. By optimization of MAE, MRP and UAAH processes, the anthocyanins reached the yield of 6.081 ± 0.106 mg/g, the purity of 78.54 ± 0.62 % (w/w) and the content of 76.29 ± 1.31 % (w/w), respectively. With high-resolution UHPLC-Q-Orbitrap/MS, 15 anthocyanins were identified as pelargonins with diverse glucosides and confirmed by pelargonidin standard. By glycosylation, pelargonins exhibited higher stability in different pH, temperature, light, metal ions environments than that of pelargonidin. However, PL inhibitory assay, kinetic analysis and molecular docking demonstrated that pelargonidin had higher PL inhibitory activity than pelargonins even though with similar binding sites and a dose–effect relationship. The above results revealed that the effect of glycosylation and deglycosylation on PL inhibitory activity and physicochemical stability.

Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on Aβ40 and Aβ42 Cofibrillation.

The misfolding and aggregation of amyloid-β (Aβ) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Aβ40 and Aβ42, the two primary isoforms of Aβ, can not only self-aggregate into homogeneous aggregates but also coaggregate to form mixed fibrils. Epigallocatechin-3-gallate (EGCG), a prominent tea polyphenol, has shown the capability to prevent the self-aggregation of Aβ40 and Aβ42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of Aβ40 and Aβ42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of Aβ40 and Aβ42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of Aβ40 and Aβ42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on Aβ40 and Aβ42 are the polar residues and aromatic residues, engaging in hydrogen-bond , π-π, and cation-π interactions with EGCG. Additionally, EGCG disaggregates the Aβ40-Aβ42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and Aβ40-Aβ42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of Aβ isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.

SiteMine: Large-scale binding site similarity searching in protein structure databases.

Drug discovery and design challenges, such as drug repurposing, analyzing protein-ligand and protein-protein complexes, ligand promiscuity studies, or function prediction, can be addressed by protein binding site similarity analysis. Although numerous tools exist, they all have individual strengths and drawbacks with regard to run time, provision of structure superpositions, and applicability to diverse application domains. Here, we introduce SiteMine, an all-in-one database-driven, alignment-providing binding site similarity search tool to tackle the most pressing challenges of binding site comparison. The performance of SiteMine is evaluated on the ProSPECCTs benchmark, showing a promising performance on most of the data sets. The method performs convincingly regarding all quality criteria for reliable binding site comparison, offering a novel state-of-the-art approach for structure-based molecular design based on binding site comparisons. In a SiteMine showcase, we discuss the high structural similarity between cathepsin L and calpain 1 binding sites and give an outlook on the impact of this finding on structure-based drug design. SiteMine is available at https://uhh.de/naomi.

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae.

γ-Aminobutyric acid type A receptors (GABAARs) are members of the pentameric ligand-gated ion channel (pLGIC) family, which are widespread throughout the invertebrate and vertebrate central nervous system. GABAARs are engaged in short-term changes of the neuronal concentrations of chloride (Cl-) and bicarbonate (HCO3 -) ions by their passive permeability through the ion channel pore. GABAARs are regulated by various structurally diverse phenolic substances ranging from simple phenols to complex polyphenols. The wide chemical and structural variability of phenols suggest similar and different binding sites on GABAARs, allowing them to manifest themselves as activators, inhibitors, or allosteric ligands of GABAAR function. Interest in phenols is associated with their great potential for GABAAR modulation, but also with their subsequent negative or positive role in neurological and psychiatric disorders. This review focuses on the GABAergic deficit hypotheses during neurological and psychiatric disorders induced by various phenols. We summarize the structure-activity relationship of general phenol groups concerning their differential roles in the manifestation of neuropsychiatric symptoms. We describe and analyze the role of GABAAR subunits in manifesting various neuropathologies and the molecular mechanisms underlying their modulation by phenols. Finally, we discuss how phenol drugs can modulate GABAAR activity via desensitization and resensitization. We also demonstrate a novel pharmacological approach to treat neuropsychiatric disorders via regulation of receptor phosphorylation/dephosphorylation.

In silico assessments of bioactive compounds from Dayak onion (Eleutherine bulbosa) as antibacterial agents targeting UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA)

Antibiotic resistance is a formidable global health challenge, a concern that also occurs in Indonesia. Dayak onion (Eleutherine bulbosa), a traditional medicinal plant, holds promising potential as a natural remedy. This study focused on in silico assessment on the antibacterial potential of Dayak onion metabolites as future antibiotics. MurA protein (PDB ID: 1UAE) was selected as the target protein. Eleuthoside C displayed the most favorable binding with a remarkably low ΔG value of -10.5 kcal/mol, denoting robust stability, followed by Eleutherinoside A (-10.1 kcal/mol) and 2,5-dimethyl-10-hydroxynaphtopyrone 8-O-β-glucopyranoside (-10.0 kcal/mol). In contrast, the standard drug fosfomycin showed a lower binding affinity (-4.6 kcal/mol). Eleuthoside C demonstrated 100% of binding site similarity (%BSS), closely followed by Eleuthoside B (91.30%), Eleutherinoside A (78.26%) and Eleutherinoside B (78.26%), with the main target to Cys115. The druglikeness criteria was only fulfilled by Eleutherinoside A, yet being proposed as the alternative lead compound for antibiotic treatment of pathogenic bacteria.

Ligand Profiling to Characterize Different Polymorphic Forms of α-Synuclein Aggregates.

The presence of amyloid fibrils is a characteristic feature of many diseases, most famously neurodegenerative disease. The supramolecular structure of these fibrils appears to be disease-specific. Identifying the unique morphologies of amyloid fibrils could, therefore, form the basis of a diagnostic tool. Here we report a method to characterize the morphology of α-synuclein (αSyn) fibrils based on profiling multiple different ligand binding sites that are present on the surfaces of fibrils. By employing various competition binding assays, seven different types of binding sites were identified on four different morphologies of αSyn fibrils. Similar binding sites on different fibrils were shown to bind ligands with significantly different affinities. We combined this information to construct individual profiles for different αSyn fibrils based on the distribution of binding sites and ligand interactions. These results demonstrate that ligand-based profiling can be used as an analytical method to characterize fibril morphologies with operationally simple fluorescence binding assays.

PoSSuM v.3: A Major Expansion of the PoSSuM Database for Finding Similar Binding Sites of Proteins.

Information on structures of protein-ligand complexes, including comparisons of known and putative protein-ligand-binding pockets, is valuable for protein annotation and drug discovery and development. To facilitate biomedical and pharmaceutical research, we developed PoSSuM (https://possum.cbrc.pj.aist.go.jp/PoSSuM/), a database for identifying similar binding pockets in proteins. The current PoSSuM database includes 191 million similar pairs among almost 10 million identified pockets. PoSSuM drug search (PoSSuMds) is a resource for investigating ligand and receptor diversity among a set of pockets that can bind to an approved drug compound. The enhanced PoSSuMds covers pockets associated with both approved drugs and drug candidates in clinical trials from the latest release of ChEMBL. Additionally, we developed two new databases: PoSSuMAg for investigating antibody-antigen interactions and PoSSuMAF to simplify exploring putative pockets in AlphaFold human protein models.