Diverse Compounds Research Articles

Assessment of volatile compounds variability among two Commiphora species using gas chromatography coupled with chemometric analysis and their biological activities

ABSTRACT Commiphora wightii is an important medicinal plant often widely used in ayurvedic medicines. However, the chemical constituents of the essential oil (EOs) obtained from C. agallocha were not well explored. Therefore, the present study aims to get an extreme understanding of the comparative volatile composition of different accessions of two important Commiphora species, namely C. wightii and C. agallocha, using gas chromatography-mass spectrometry (GC-MS), followed by multivariate principal component analysis and partial least squares discriminant analysis-based chemometric analysis. A total of 129 diverse volatile organic compounds (VOCs) were identified in EOs of both Commiphora species, and the concentration of VOCs varied significantly from species to species as well as from accession to accession. In C. wightii EO, 80 compounds were identified, containing sesquiterpenes followed by diterpenes, whereas 49 compounds were identified in C. agallocha EO with high sesquiterpene levels. The GC-MS and chemometric analyses distinguished C. wightii and C. agallocha species based on their qualitative and quantitative variations in terpenoid contents. Both EOs exhibited promising antioxidant activity to the positive standard butylated hydroxyl toluene. The EOs of the Commiphora species exhibited antimicrobial activities in disc diffusion and biofilm assays against two bacterial and one fungal strain; however, C. wightii EO displayed a strong inhibitory effect against Klebsiella pneumoniae, Pseudomonas aeruginosa and Candida albicans compared to other EOs. In this study, we first reported the comprehensive profiling of terpenoid content of C. wightii and C. agallocha stems along with their antibiofilm activity against two pathogenic bacterial strains and one fungal strain in a comparative manner. Based on the comparative antimicrobial assay between two Commiphora species, the EO of C. wightii showed good biofilm inhibition potential against Klebsiella pneumoniae, Pseudomonas aeruginosa and Candida albicans compared with EO of C. agallocha. Based on the current results, the two Commiphora species may be promising ingredients for applications in the pharmaceutical industry.

Molecular insights into a distinct class of terpenoid cyclases

Terpenoid cyclases (TCs) account for the synthesis of the most widespread and diverse natural compounds. A sesquiterpene cyclase termed BcABA3 from an abscisic acid-producing fungus Botrytis cinerea that yields (2Z,4E)-α-ionylideneethane but lacks signature feature of canonical TCs represents a distinct type of TCs. Here, we report the crystal structures of BcABA3, a closely related RuABA3 from Rutstroemia sp. and a bacterial SkABA3 from Shimazuella kribbensis. These ABA3 proteins adopt an all-α-helix fold and bind pyrophosphate moiety of farnesyl pyrophosphate by Glu-chelated Mg2+ ion cluster. We conduct mutagenesis experiments to validate the role of the substrate-binding residues. SkABA3 appears to yield compounds that are distinct from (2Z,4E)-α-ionylideneethane. These results not only provide the molecular insight into ABA3 proteins that serve as an important basis to the future investigation of this class of TCs, but also reveal the existence of more uncharacterized terpenoids synthesized via dedicated machineries.

Virtual Screening Identifies Inhibitors of SARS-CoV-2 Main Protease through Pharmacophore and Similarity Approaches.

The emergence of SARS-CoV-2 and the COVID-19 pandemic highlighted the urgent need for novel antiviral therapies. The main protease (Mpro) of SARS-CoV-2 is a key enzyme in viral replication and a promising therapeutic target. This study employed virtual screening approaches to identify potential Mpro inhibitors, leveraging both structure- and ligand-based methods. Two optimum pharmacophore models were built from hundreds of crystallographic structures of Mpro, validated through ROC curve analysis and Dynophores dynamic simulations. These models captured ≈ 60K hits from six diverse compound libraries made of more than 3 million compounds. Additionally, a ligandbased similarity search using ROCS software identified 1024 potential hits based on shape and atom-based comparisons with co-crystallized ligands. Subsequent molecular docking and filtering based on physicochemical properties and structural diversity yielded 16 and 6 hits from structure- and ligand-based screening, respectively. Molecular dynamics simulations were conducted on the top-scoring hits to assess their binding stability within the Mpro active site. SCR00943 demonstrated stable binding, interacting favorably with key residues, including the catalytic dyad, resulting in a binding affinity of -61.2 kcal/mol. This virtual screening campaign identified promising Mpro inhibitors, showcasing the potential of computational approaches to accelerate drug discovery efforts against COVID-19.

Cosmopolitan but still untapped: Antimicrobial, antibiofilm and in silico molecular docking study on Caulerpa racemosa, Dictyopteris polypodioides and Padina pavonica

Cosmopolitan but still untapped: Antimicrobial, antibiofilm and in silico molecular docking study on Caulerpa racemosa, Dictyopteris polypodioides and Padina pavonica

Anthocyanin and phenolic landscape of Syzygium cumini extracts via green extraction.

This study determined the anthocyanin and phenolic profile of Syzygium cumini bioactive compounds, including anthocyanins and other flavonoids, alongside diverse phenolic compounds. The study optimized a green extraction technique (ultrasound-assisted enzymatic extraction (UAEE)) to obtain anthocyanin-rich extract from the fruit pulp of S. cumini using the pectinase enzyme. UHPLC-LC/MS, FTIR, and SEM were used to profile the secondary metabolites, functional groups, and surface morphology. Two major anthocyanins, cyanidin and malvidin, and twenty-three non-anthocyanins, including gallic acid, naringenin, myricetin, and kaempferol, were identified in the enzymatic extract of S. cumini. A central-composite design was used to optimize the extraction, analyzing the effects of enzyme concentration (0.01-0.03%), pH (1-3), and ultrasonication time (5-15min) on total anthocyanin content (438.75±29.81mg C3G/100g db), determining the optimal points (0.01%, 2 pH and 10 mins). The optimized extract was further investigated for total phenolic content and antioxidant activities. The study utilized an economical approach to effectively extract maximum anthocyanins from S. cumini fruit for their potential applications as a biocolorant in food products, simultaneously establishing promising health potential through available literature.

Chemical Characterization and Differential Lipid-Modulating Effects of Selected Plant Extracts from Côa Valley (Portugal) in a Cell Model for Liver Steatosis.

Côa Valley, located in the northeast of Portugal, harbors more than 500 medicinal plant species. Among them, four species stand out due to their traditional uses: Equisetum ramosissimum Desf. (hemorrhages, urethritis, hepatitis), Rumex scutatus L. subsp. induratus (Boiss. and Reut.) Malag. (inflammation, constipation), Geranium purpureum Vill., and Geranium lucidum L. (pain relief, gastric issues). Given their rich ethnomedicinal history, we evaluated their protective effects on an in vitro model of metabolic dysfunction-associated steatotic liver disease (MASLD). Decoction (D) and hydroalcoholic (EtOH80%) extracts were prepared and chemically characterized. Their safety profile and effects on lipid accumulation were assessed in palmitic acid (PA)-treated HepG2 cells using resazurin, sulforhodamine B, and Nile Red assays. Chemical analysis revealed diverse phenolic compounds, particularly kaempferol derivatives in E. ramosissimum. All extracts showed minimal cytotoxicity at 25-50 µg/mL. At 100 µg/mL, only E. ramosissimum extracts maintained high cell viability. In the lipotoxicity model, E. ramosissimum decoction demonstrated the most potent effect, significantly reducing PA-induced neutral lipid accumulation in a dose-dependent manner, while other extracts showed varying degrees of activity. These findings highlight E. ramosissimum's decoction, rich in kaempferol derivatives, as particularly effective in reducing lipid accumulation in this MASLD cell model while also providing a comprehensive characterization of traditionally used plants from the Côa Valley region.

Cobalt-catalyzed regio- and diastereoselective carbocyclization/arylation of 1,5-bisallenes

The first non-precious cobalt-catalyzed carbocyclization/arylation of 1,5-bisallenes has been developed, affording cis-disubstituted pyrroles with high regio- and diastereoselectivity.

REDOX POTENTIAL STUDIES BASED ON SCAN-RATE ANALYSIS OF THE DIFFUSIONAL CONTROL AND DFT CALCULATIONS OF THE SCHIFF BASE [(E)-4-AMINO-3-((3,5-DI-tert-BUTYL-2- HYDROXYBENZYLIDENE)AMINO) BENZOIC ACID

Schiff bases are diverse organic compounds with an azomethine structure (–C=N–), holding potential in both chemistry and biology. They serve as catalysts, stabilizers, and exhibit various biological activities. The molecular structure of Schiff bases influences their biological properties, including antimicrobial effects. Redox-active compounds with more negative potentials tend to be more effective against microbes. In one of our recent studies, we explored the antimicrobial properties of two Schiff bases derivatives, SB-1 ((E)-4-amino-3-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino) and SB-2 ((E)-2-((4-nitrobenzilidene)amino)aniline). SB-1 showed antibacterial activity against certain Gram-positive bacteria, while SB-2 did not. The difference in their cyclic voltametric profiles, especially SB-1’s more negative reduction potential, prompted us to carry out further characterizations, including scan-rate studies, solvent analysis, and computational calculations. We found that SB-1, which presents a stable intramolecular hydrogen bond, undergoes irreversible oxidation, likely at the –NH2 group, and a quasi-reversible reduction via an intramolecular reductive coupling of the (–C=N–) azomethine group, supported by orbital theoretical calculations. This research sheds light on the potential applications of Schiff bases in antimicrobial contexts, guided by their redox properties and structure.

Simultaneous Quantitative Determination of Five Process Relevant Impurities in Menatetrenone

ABSTRACTMenatetrenone, a form of vitamin K (MK‐4) is used for various pharmaceutical and agrochemical applications. Monitoring and control of process impurities is crucial in the manufacturing of pharmaceutical‐grade Menatetranone. In this article, we report a gas chromatography (GC)‐based analytical method for the detection and quantification of trace levels of five process‐related impurities in MK‐4 originating from the starting materials and reagents. A GC‐flame ionization detector (GC‐FID)‐based method is presented for simultaneous quantitative estimation of five structurally diverse compounds, some of which are conventionally analyzed by liquid chromatography. After a series of method development trials, an optimized method with a mid‐polar column dura bond‐624 (6% cyanopropyl/phenyl and 94% polydimethylsiloxane) with initial column oven temperature 150°C, detector temperature 280°C was finalized for the separation of these impurities. The developed GC‐FID‐based method was validated for specificity, the limit of detection (LOD), the limit of quantification (LOQ), linearity, range, precision, accuracy, and robustness as relevant to the International Council for Harmonization guidelines. The method was found to be highly sensitive for all the constituents with an LOD ranging from 0.05 to 0.43 pg and a limit of quantification of 0.17–1.41 pg, as estimated by the signal‐to‐noise ratios. This is the first report of an analytical method for the simultaneous quantitative determination of five process impurities of MK‐4.

Widespread presence of metallic compounds and organic contaminants across Pacific coral reef fish.

Coral reef fishes represent an invaluable source of macro- and micro-nutrients for tropical coastal populations. However, several potentially toxic compounds may jeopardize their contribution to food security. Concentrations of metallic compounds and trace elements (MTEs), and persistent organic pollutants (POPs, including pesticides and polychlorobiphenyls PCBs), totalizing 36 contaminants, were measured in coral reef fish from several Pacific islands. The objective of this study was to describe the spatial distribution of these compounds and contaminants in order to identify potential variables explaining their distribution at a Pacific-wide scale. To achieve this, we applied Boosted Regression Trees to model species-specific and community-level contaminant and inorganic compound concentrations at the scale of the tropical Pacific Ocean. Overall, using 15 easily accessible explanatory variables, we successfully explained between 60 and 87% of the global variation, with fish body size being the most important correlate of MTEs and POPs concentrations in reef fish. Our modeling approach allowed us to estimate and map the distribution of the community-level concentration of 19 contaminants and inorganic compounds at the scale of the equatorial and south Pacific Ocean. Spatial patterns varied significantly depending on the compound, with modeled quantities per 100g of fish flesh generally being higher in the central and southwest Pacific than in the eastern part of the basin. These patterns were influenced by a combination of biological, environmental, anthropogenic and biogeographical variables. Overall, this approach represents an important step toward the estimation of concentrations of the main compounds on the basis of species identity and fishing location. Our results enhance our understanding of the extent of contamination in the Pacific while underscoring the urgent need for long-term and large-scale spatial monitoring of diverse compounds in this region.

Synthesis and characterization of novel 5-substituted indanones via Suzuki coupling reactions

Abstract 1-Indanone and its derivatives are well known for their diverse biological activities, making them valuable scaffolds in drug design and medicinal chemistry. Among the various synthetic methodologies available for modifying such structures, the Suzuki-Miyaura cross-coupling reaction is a prominent approach for constructing carbon-carbon bonds. In this study, the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of 5-bromo-1-indanone with four different boronic acids—phenylboronic acid, 4-methoxyphenylboronic acid, 4-thiomethylphenylboronic acid, and 4-ethylphenylboronic acid—was investigated. The reactions yielded the corresponding 5-substituted indanone derivatives, which were characterized by 1H and 13C NMR spectroscopy to confirm their structures and assess their purity. This study demonstrates the efficiency and versatility of the Suzuki-Miyaura reaction in functionalizing 1-indanone derivatives, providing a robust route for synthesizing structurally diverse compounds with potential applications in medicinal chemistry. The newly synthesized and characterized 5-indanone derivatives have potential applications in the development of new drug candidates. These compounds may contribute to advancements in treatments for various diseases, including cancer and Alzheimer’s disease, by integrating into biologically active structures.

Genomic and metabolic characterization of Trueperella pyogenes isolated from domestic and wild animals.

Trueperella pyogenes is an important bacterial pathogen implicated in infections such as mastitis, metritis, pneumonia, and liver abscesses in both domestic and wild animals, as well as endocarditis and prosthetic joint infections in humans. Understanding the genomic and metabolic features that enable T. pyogenes to colonize different anatomical sites within a host and its inter-kingdom transmission and survival is important for the effective control of this pathogen. We employed whole-genome sequencing, phenotype microarrays, and antimicrobial susceptibility testing to identify genomic, metabolic and phenotypic features, and antimicrobial resistance (AMR) genes in T. pyogenes recovered from different livestock, companion, and wildlife animals. For comparative genomic analysis, 83 T. pyogenes genomes, including 60 isolated in the current study and 23 publicly available genomes were evaluated. These genomes represented T. pyogenes strains originating from 16 different body sites of 11 different animal hosts (e.g., cattle, swine, ovine, deer, bison, horse, chamois, and cat). Additionally, 49 T. pyogenes isolates (cattle, sheep, deer, swine, and cats) were evaluated for phenotypic AMR using disk diffusion, and for metabolic profiling using the Biology GENIII MicroPlates. The T. pyogenes strains were found not to be host- or body site-specific. The presence of conserved virulence genes (plo and fimA), as well as genotypic and phenotypic AMR may contribute to the ability of T. pyogenes to cause infections in livestock, wildlife, and pets. Most of the tested isolates metabolized diverse carbon sources and chemical compounds, suggesting that this metabolic versatility may enhance the survival, competitiveness, and pathogenic potential of T. pyogenes.IMPORTANCETrueperella pyogenes is an important animal pathogen with zoonotic potential, posing a significant health concern to both animals and humans due to its ability to cause infections across different animal host species and tissues. Current understanding of this pathogen's adaptability and survival mechanisms is limited. Here, we evaluated the genomic, virulence, metabolic, and antimicrobial resistance (AMR) characteristics of T. pyogenes recovered from 16 different body sites of 11 different animal hosts (livestock, companion, and wild animals). We identified multiple AMR and virulence genes that may enable T. pyogenes for sustained infection and transmission. Additionally, T. pyogenes strains displayed metabolic versatility which could also contribute to its ability to thrive in diverse environments. Understanding the genomic and metabolic, and AMR characteristics that enable T. pyogenes to colonize different anatomical sites within a host and its transmission between different animal species is important for the effective control of this pathogen.

Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels

ABSTRACT Vascular smooth muscle ATP-sensitive potassium (KATP) channels play critical roles in modulating vascular tone and thus represent important drug targets for diverse cardiovascular pathologies. Despite extensive research efforts spanning several decades, the search for selective inhibitors that can discriminate between vascular KATP (i.e. Kir6.1/SUR2B) and pancreatic and brain KATP (i.e. Kir6.2/SUR1) channels has, until recently, been unsuccessful. Our group therefore carried out a high-throughput screen of chemically diverse compounds with the goal of discovering specific Kir6.1/SUR2B inhibitors. This screen identified several novel classes of Kir6.1/SUR2B inhibitors, including the first potent (IC50 ~100 nM) and selective inhibitor published to date, termed VU0542270. Here, we expand on this work by disclosing the identity and pharmacological properties of four additional Kir6.1/SUR2B inhibitors that are structurally unrelated to Kir to VU0542270. These inhibitors, named VU0212387, VU0543336, VU0605768, and VU0544086, inhibit Kir6.1/SUR2B with IC50 values ranging from approximately 100 nM to 1 µM and exhibit no apparent inhibitory activity toward Kir6.2/SUR1. Functional analysis of heterologously expressed subunit combinations of Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B and demonstrated that all four inhibitors act on SUR2 to induce channel inhibition. Interestingly, VU0543336 and VU0212387 exhibit paradoxical stimulatory effects on Kir6.2/SUR1 at higher doses. This study broadens our understanding of KATP channel pharmacology, generally, and reveals novel chemical matter for the development of Kir6.1/SUR2-selective drugs, specifically.

Secondary metabolite profiling, antioxidant, and anti-inflammatory investigations of Symplocos paniculata (Thunb.) Miq., an ethnomedicinal plant from Kumaun Himalayan region

Background: Traditional medicine relies heavily on plant-based remedies for immune system modulation, offering advantages of affordability, reduced toxicity, minimal side effects, and better accessibility compared to synthetic alternatives. Symplocos paniculata (Thunb.) Miq. has been traditionally used in ethnomedicine for various ailments, though its chemical composition and therapeutic properties remain inadequately studied. Objectives: Thus, this study aimed to investigate the phytochemical composition and evaluate the antioxidant and anti-inflammatory properties of leaf and bark extracts from S. paniculata. Material and Methods: The study employed qualitative and quantitative phytochemical screening methods, along with in vitro assays including DPPH radical scavenging and metal chelation for antioxidant activity, and protein denaturation for anti-inflammatory effects. GC-MS analysis was conducted to identify the phytoconstituents. Results and Conclusion: Phytochemical screening revealed diverse compounds, with leaf extracts showing higher concentrations of phenolics, flavonoids, and tannins compared to bark extracts. Bark extract demonstrated superior antioxidant properties with DPPH radical scavenging (IC50 = 61.37 μg/ml) and metal chelating (IC50 = 30.06 μg/ml) activities. Moderate anti-inflammatory activity was observed, with leaf extract showing slightly higher potency (IC50 = 222.81 μg/ml). GC-MS analysis identified terpenes, phytosterols, and fatty acids as major constituents in both extracts. The study provides scientific validation for traditional medicinal applications of S. paniculata through comprehensive characterization of its phytochemical profile and demonstration of significant antioxidant and anti-inflammatory properties, establishing its potential for pharmaceutical development.

Unveiling the pharmacological potential of guava (Psidium guajava L.): A review

Guava, a tropical fruit renowned for its rich nutritional profile, has garnered increasing attention in the field of pharmacology due to its diverse bioactive compounds. This resilient plant flourishes in tropical and subtropical climates, making it well-suited to warm environments. Guavas are climacteric fruits, which means they continue to ripen after being harvested. They are renowned for their nutritional profile, rich in potassium, lycopene, manganese, iron, calcium, fiber and essential vitamins and minerals. The guava plant's fruit and leaves possess a range of edible and medicinal properties. Guava extracts are recognized for their health benefits, which include anticancer, antiobesity, antibacterial, antidiabetic and antihypertensive effects. The presence of phytochemicals in guava leaves, such as caffeic acid, flavonoids and hyperin, enhances their therapeutic potential, particularly in treating respiratory ailments like coughs and colds. Guava’s impressive health-promoting qualities have made it a valuable addition to traditional medicine practices. Its fruits are not only delicious but also serve as a natural remedy for various conditions, highlighting the plant's versatility. By incorporating guava into the diet, individuals can benefit from its wide-ranging health advantages, making it a worthwhile fruit to include in daily nutrition. Overall, guava stands out as a powerhouse of nutrients and therapeutic properties, contributing significantly to health and wellness.

Oxygen is toxic in the cold in C. elegans.

Temperature and oxygen are two factors that profoundly affect survival limits of animals; too much or too little of either is lethal. However, humans and other animals can exhibit exceptional survival when oxygen and temperature are simultaneously low. This research investigates the role of oxygen in the cold shock death of Caenorhabditis elegans. The survival of C. elegans populations in combinations of oxygen concentrations and was assayed. Additionally, the effect of cold acclimatization, mutations in the cold acclimatization pathway, compounds, and antioxidant proteins on survival in low temperatures and high oxygen were investigated. We demonstrate that C. elegans have increased survival in 2°C when deprived of oxygen, and an increase to just 0.25kPa of oxygen decreased survival. Additionally, we show that oxygen toxicity produced by a 35-fold increase above atmospheric oxygen levels was fatal for nematodes in 8h at room temperature and 2h at 2°C. We found that cold acclimatization and mutations in the cold acclimatization pathway improve survival in room temperature oxygen toxicity. Furthermore, we found that the compounds glucose, manganese (II), and ascorbate improve both cold shock and high oxygen survival, while the antioxidant proteins catalase and peroxiredoxin are essential to wild type survival in these conditions. Our results suggest that oxygen toxicity contributes to the death of C. elegans during cold shock. The changes in survival induced by cold acclimatization and mutations in the cold acclimatization pathway suggest that oxygen toxicity in the cold exerts evolutionary pressure, leading to the development of protections against it. Additionally, the resistance provided by diverse compounds and antioxidant proteins in both low temperature and high oxygen suggests these conditions have similar chemical environments. We discuss evidence that similar phenomena may function in humans.

SpaceHASTEN: A Structure-Based Virtual Screening Tool for Nonenumerated Virtual Chemical Libraries.

Given the size of the relevant chemical space for drug discovery, working with fully enumerated compound libraries (especially in three-dimensional (3D)) is unfeasible. Nonenumerated virtual chemical spaces are a practical solution to this issue, where compounds are described as building blocks which are then connected by rules. One concrete example of such is the BioSolveIT chemical spaces file format (.space). Tools to search these space-files exist that are using ligand-based methods including two-dimensional (2D) fingerprint similarity, substructure matching, and fuzzier similarity metrics such as FTrees. However, there is no software available that enables the screening of these nonenumerated spaces using protein structure as the input query. Here, a hybrid ligand/structure-based virtual screening tool, called SpaceHASTEN, was developed on top of SpaceLight, FTrees, LigPrep, and Glide to allow efficient structure-based virtual screening of nonenumerated chemical spaces. SpaceHASTEN was validated using three public targets picked from the DUD-E data set. It was able to retrieve a large number of diverse and novel high-scoring compounds (virtual hits) from nonenumerated chemical spaces of billions of molecules, after docking a few million compounds. The software can be freely used and is available from http://github.com/TuomoKalliokoski/SpaceHASTEN.

A review on 2-arylidene-1,3-indanediones: preparation and applications to the synthesis of diverse spirocyclic compounds

A review on 2-arylidene-1,3-indanediones: preparation and applications to the synthesis of diverse spirocyclic compounds

Interface-aware molecular generative framework for protein–protein interaction modulators

Protein–protein interactions (PPIs) play a crucial role in numerous biochemical and biological processes. Although several structure-based molecular generative models have been developed, PPI interfaces and compounds targeting PPIs exhibit distinct physicochemical properties compared to traditional binding pockets and small-molecule drugs. As a result, generating compounds that effectively target PPIs, particularly by considering PPI complexes or interface hotspot residues, remains a significant challenge. In this work, we constructed a comprehensive dataset of PPI interfaces with active and inactive compound pairs. Based on this, we propose a novel molecular generative framework tailored to PPI interfaces, named GENiPPI. Our evaluation demonstrates that GENiPPI captures the implicit relationships between the PPI interfaces and the active molecules, and can generate novel compounds that target these interfaces. Moreover, GENiPPI can generate structurally diverse novel compounds with limited PPI interface modulators. To the best of our knowledge, this is the first exploration of a structure-based molecular generative model focused on PPI interfaces, which could facilitate the design of PPI modulators. The PPI interface-based molecular generative model enriches the existing landscape of structure-based (pocket/interface) molecular generative model.Scientific contributionThis study introduces GENiPPI, a protein-protein interaction (PPI) interface-aware molecular generative framework. The framework first employs Graph Attention Networks to capture atomic-level interaction features at the protein complex interface. Subsequently, Convolutional Neural Networks extract compound representations in voxel and electron density spaces. These features are integrated into a Conditional Wasserstein Generative AdversarialNetwork, which trains the model to generate compound representations targeting PPI interfaces. GENiPPI effectively captures the relationship between PPI interfaces and active/inactive compounds. Furthermore, in fewshot molecular generation, GENiPPI successfully generates compounds comparable to known disruptors. GENiPPI provides an efficient tool for structure-based design of PPI modulators.

Biological Implications of the Intrinsic Deformability of Human Acetylcholinesterase Induced by Diverse Compounds: A Computational Study.

The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors was investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks (ENM and NMA), statistical potentials (CUPSAT and SWOTein), energy frustration (Frustratometer), and volumetric cavity analyses (MOLE and PockDrug). The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.