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Atherosclerotic cardiovascular diseases (CVDs) are closely linked to factors such as familial hypercholesterolemia (FH), often caused by mutations in low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB). Through a comprehensive bioinformatic analysis, we identified novel LDLR and APOB mutations and their cardiovascular disease (CVD) implications, focusing on unique variants in the Vietnamese population. We used homology modeling to predict protein structures; in addition, through protein-protein molecular docking, we assessed how these mutations affect binding affinities. We identified 10 novel binding residues exclusive to the wild-type and precursor LDLR isoforms, including ASP-47, GLY-48, and GLU-51. Analyses of 154 complexes revealed 5 isoforms with low binding affinities and notable hydrogen-bonding interactions—APOB (Arg3527Trp)-LDLR (Cys318Arg), APOB (His3583Leu)-LDLR (Cys104Tyr), APOB wild-LDLR (Glu228Lys), APOB (Phe2469Cys)-LDLR (Glu288Lys), and APOB wild-LDLR (Ser130Ter). These results suggest strong and potentially detrimental interactions among these proteins. Furthermore, they highlight the molecular mechanisms underlying CVD development, reveal potential therapeutic targets, enhance our understanding of genetic variations, and could guide FH research. [ABSTRACT FROM AUTHOR]

ABSTRACT Bayoud disease, which is caused by the fungus Fusarium oxysporum f. sp. albedinis (FOA), is a severe threat to date palm cultivation in North Africa and the Middle East; thus, effective antifungal treatments are urgently required. In response to this, the present study develops, characterizes, and tests imidazo[1,2‐a]pyrimidine–Schiff base derivatives as potential antifungal compounds. A series of these derivatives (labeled IMP‐1 to IMP‐6) was obtained using a facile conventional synthetic route that holds the potential for scalable production. The structures of the samples were characterized using traditional spectroscopic techniques, while IMP‐1 and IMP‐3 were subjected to single‐crystal X‐ray diffraction analysis to verify the structural assignment of the synthesized compounds. Screening analysis of the antifungal activity of the IMPs against FOA demonstrated remarkable inhibition effects, with IC50 values ranging from 4.7 to 2.6 μg/mL. In particular, IMP‐6 demonstrated exceptional potency, with an inhibition rate exceeding 97% at a low concentration of only 16.42 μM, thus outperforming many previously reported antifungal compounds. Homology modeling and molecular docking analysis were also conducted to understand how these novel antifungal agents interact with their target, with the experimental and theoretical approaches producing consistent results. [ABSTRACT FROM AUTHOR]

Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity. [ABSTRACT FROM AUTHOR]

FFA4 has gained interest in recent years since its deorphanization in 2005 and the characterization of the Free Fatty Acids receptors family for their therapeutic potential in metabolic disorders. The expression of FFA4 (also known as GPR120) in numerous organs throughout the human body makes this receptor a highly potent target, particularly in fat sensing and diet preference. This offers an attractive approach to tackle obesity and related metabolic diseases. Recent cryo‐EM structures of the receptor have provided valuable information for a potential active state although the previous studies of FFA4 presented diverging information. We performed molecular docking and molecular dynamics simulations of four agonist ligands, TUG‐891, Linoleic acid, α‐Linolenic acid, and Oleic acid, based on a homology model. Our simulations, which accumulated a total of 2 μs of simulation, highlighted two binding hotspots at Arg992.64 and Lys293 (ECL3). The results indicate that the residues are located in separate areas of the binding pocket and interact with various types of ligands, implying different potential active states of FFA4 and a highly adaptable binding intra‐receptor pocket. This article proposes additional structural characteristics and mechanisms for agonist binding that complement the experimental structures. [ABSTRACT FROM AUTHOR]

Chemical communication using pheromones is thought to have contributed to the diversification and speciation of insects. The species-specific pheromones are detected by specialized pheromone receptors (PRs). Whereas the evolution and function of PRs have been extensively studied in Lepidoptera, only a few PRs have been identified in beetles, which limits our understanding of their evolutionary histories and physiological functions. To shed light on these questions, we aimed to functionally characterize potential PRs in the spruce bark beetle Ips typographus ("Ityp") and explore their evolutionary origins and molecular interactions with ligands. Males of this species release an aggregation pheromone comprising 2-methyl-3-buten-2-ol and (4 S)- cis- verbenol, which attracts both sexes to attacked trees. Using two systems for functional characterization, we show that the highly expressed odorant receptor (OR) ItypOR41 responds specifically to (4 S)- cis- verbenol, with structurally similar compounds eliciting minor responses. We next targeted the closely related ItypOR40 and ItypOR45. Whereas ItypOR40 was unresponsive, ItypOR45 showed an overlapping response profile with ItypOR41, but a broader tuning. Our phylogenetic analysis shows that these ORs are present in a different OR clade as compared to all other known beetle PRs, suggesting multiple evolutionary origins of PRs in bark beetles. Next, using computational analyses and experimental validation, we reveal two amino acid residues (Gln179 and Trp310) that are important for ligand binding and pheromone specificity of ItypOR41 for (4 S)- cis -verbenol, possibly via hydrogen bonding to Gln179. Collectively, our results shed new light on the origins, specificity, and ligand binding mechanisms of PRs in beetles. [ABSTRACT FROM AUTHOR]

Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti‐tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor‐bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross‐correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor‐bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation. [ABSTRACT FROM AUTHOR]

Even though COVID-19 is no longer the primary focus of the global scientific community, its high mutation rate (nearly 30 substitutions per year) poses a threat of a potential comeback. Effective vaccines have been developed and administered to the population, ending the pandemic. Nonetheless, reinfection by newly emerging subvariants, particularly the latest JN.1 strain, remains common. The rapid mutation of this virus demands a fast response from the scientific community in case of an emergency. While the immune escape of earlier variants was extensively investigated, one still needs a comprehensive understanding of how specific mutations, especially in the newest subvariants, influence the antigenic escape of the pathogen. Here, we tested comprehensive in silico approaches to identify methods for fast and accurate prediction of antibody neutralization by various mutants. As a benchmark, we modeled the complexes of the murine antibody 2B04, which neutralizes infection by preventing the SARS-CoV-2 spike glycoprotein’s association with angiotensin-converting enzyme (ACE2). Complexes with the wild-type, B.1.1.7 Alpha, and B.1.427/429 Epsilon SARS-CoV-2 variants were used as positive controls, while complexes with the B.1.351 Beta, P.1 Gamma, B.1.617.2 Delta, B.1.617.1 Kappa, BA.1 Omicron, and the newest JN.1 Omicron variants were used as decoys. Three essentially different algorithms were employed: forced placement based on a template, followed by two steps of extended molecular dynamics simulations; protein–protein docking utilizing PIPER (an FFT-based method extended for use with pairwise interaction potentials); and the AlphaFold 3.0 model for complex structure prediction. Homology modeling was used to assess the 3D structure of the newly emerged JN.1 Omicron subvariant, whose crystallographic structure is not yet available in the Protein Database. After a careful comparison of these three approaches, we were able to identify the pros and cons of each method. Protein–protein docking yielded two false-positive results, while manual placement reinforced by molecular dynamics produced one false positive and one false negative. In contrast, AlphaFold resulted in only one doubtful result and a higher overall accuracy-to-time ratio. The reasons for inaccuracies and potential pitfalls of various approaches are carefully explained. In addition to a comparative analysis of methods, some mechanisms of immune escape are elucidated herein. This provides a critical foundation for improving the predictive accuracy of vaccine efficacy against new viral subvariants, introducing accurate methodologies, and pinpointing potential challenges.

Abstract GPRC6A, a member of the Family C G‐protein coupled receptors, regulates energy metabolism and sex hormone production and is activated by diverse ligands, including cations, L‐amino acids, the osteocalcin (Ocn) peptide and the steroid hormone testosterone. We sought a structural framework for the ability of multiple distinct classes of ligands to active GPRC6A. We created a structural model of GPRC6A using Alphafold2. Using this model we explored a putative orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain of GPRC6A and two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7 transmembrane (7TM) domain. We provide evidence that Ocn peptides act as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L‐amino acids. In agreement with this prediction, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the computationally predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations explain how dissimilar ligands activate GPRC6A and set the stage to develop novel molecules to activate and inhibit this previously poorly understood receptor.

Abstract Background Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists. Results Based on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound. Conclusions The current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism.

Background: Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medications to cure T2DM, the review of the literature found that various Pyrimidine derivatives act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic Beta-cells and its mechanism of action with fewer adverse effects. In the present research work, In-silico investigations were carried out to investigate the potential of the Pyrimidine analog as an agonist to the protein target GPR119 receptor. We performed exhaustive molecular modeling and protein modeling methodologies such as homology modeling, and molecular docking along with various drug designing tools such as 3D-QSAR and Pharmacophore Mapping to ascertain the design of better GPR119 agonists. Results: Based on in-depth computational studies, we designed new pyrimidine moiety and analyzed them for GPR119 receptor agonist and further explored the ADMET properties. Designed compounds were found to exhibit better-predicted activities as compared to reference compound. Conclusions: The current research on pyrimidine derivatives, using molecular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of − 11.696, − 9.314 and − 8.721, respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidates for the treatment of diabetes acting via the GPR119 agonist mechanism. [ABSTRACT FROM AUTHOR]

Candida auris, a fungal species, has emerged as a global menace due to its drug-resistant nature, leading to widespread invasive infections. Currently, there is no vaccine to prevent C. auris. The study was attempted to ascertain the structure and role of an unannotated hypothetical protein (HP) (accession no. QWW22972.1) from C. auris utilizing various bioinformatics tools. In this study, HP was found to be stable and polar, located in the cytoplasm. Various tools like NCBI-CD search, ScanProsite, InterPro, and SMART, identified it as a member of the Ran family of GTP-binding nuclear proteins that involves facilitating nucleocytoplasmic transport, including the import and export of proteins and RNAs during the interphase of mitosis. The protein's secondary structure analysis indicated a dominance of the alpha helix. Its three-dimensional (3D) structure, modeled via the SWISS-MODEL server using a template protein with a 94.15% sequence identity, was validated by PROCHECK, QMEAN, Verify3D, and ERRAT tools. After YASARA energy reduction, a more stable 3D structure was visible. Furthermore, protein-protein interactions were obtained from STRING server, and active site were derived from the computed atlas of surface topography of proteins server. However, this study may enhance understanding of the molecular foundation of the HP and help identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

GPRC6A, a member of the Family C G‐protein coupled receptors, regulates energy metabolism and sex hormone production and is activated by diverse ligands, including cations, L‐amino acids, the osteocalcin (Ocn) peptide and the steroid hormone testosterone. We sought a structural framework for the ability of multiple distinct classes of ligands to active GPRC6A. We created a structural model of GPRC6A using Alphafold2. Using this model we explored a putative orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain of GPRC6A and two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7 transmembrane (7TM) domain. We provide evidence that Ocn peptides act as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L‐amino acids. In agreement with this prediction, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the computationally predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations explain how dissimilar ligands activate GPRC6A and set the stage to develop novel molecules to activate and inhibit this previously poorly understood receptor. [ABSTRACT FROM AUTHOR]

Fishes are bio-concentrators for heavy metals, but cannot thrive in excessively polluted water. Heavy metals can accumulate in Arius arius, and cadmium (Cd) activates its metal-binding protein. Presently, Cd-binding metallothionein (MT) in A. arius is subjected to sub-lethal cadmium chloride (CdCl2 at 20 mg/L for 72 h). Separation of MT was achieved from liver homogenate supernatants via affinity chromatography and Sephadex G-25, assessed by 15% SDS-PAGE, verified by Western blotting, and quantified by MALDI-TOF. Using mass fingerprinting, peptide masses were searched in Swiss-Prot. A. arius bounded MT amino acid sequences matched Oreochromis mossambicus with 100%. The 60 amino acids of MT and cysteine content were identified (20 residues). MT contains 6021 daltons based on the MALDI-TOF–MS. The MT protein was modeled using modular9v8 software, confirmed using Ramachandran plot, and utilized as a biomarker for Cd toxicity in fish. The 3D structures might help to identify the binding sites and may lead to innovative treatments for stress and cadmium toxicity. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) constitute the largest protein family involved in signal transduction and are the main targets for drug delivery. The metabotropic glutamate receptors (mGluRs) are class C of GPCRs that contribute to the modulation of glutamatergic neurotransmission which regulates vital physiological processes and is recognized as a potential therapeutic target throughout the central nervous system. Intracellular C-terminal domains of mGluR are the main targets for proteins regulating these receptors and are also involved in alternative splicing, regulation by phosphorylation, and modulatory protein-protein interactions. Class C of GPCRs exist as dimers and is mediated by interactions between the venus tryflap domain and the transmembrane domain. The mGluR5 variant F can be regulated by both positive and negative allosteric modulators that can potentiate or inhibit the endogenous ligand and glutamate, respectively. Moreover, mGluR5 is involved in many disorders including fragile X syndrome/autism spectrum disorder, schizophrenia, anxiety, addiction, chronic pain and epilepsy, etc. The main purpose of current computational work is to determine the 3D structures of the target protein and their active sites to design new drug molecules as potential biochemical agents. The 3D model of the mGluR5 variant F was constructed through homology modeling techniques using MOE and I-TESSER programs. RAMPAGE and ERRATE online servers were used for the 3D structure evaluation and validation. Furthermore, the mGluR5 variant F was docked with 20 mavoglurant derivatives that act as antagonists. Mavoglurant derivatives 3, 4, 6, 10, 13, 18, and 19 showed a maximum of four interactions with the mGluR5 variant F, whereas derivatives 7, 8, 9, 11, 12, 15, 16, 17 and 20 showed a maximum of three interactions with the mGluR5 variant F. The remaining four mavoglurant derivatives expressed two interactions each with mGluR5 variant F. The docking score for these derivatives ranged between −15.55 and −08.210 kcal mol−1 suggesting their strong interactions with the mGluR5 variant F. Their 3D structure and docking study provides a potential base for the synthesis of new drug candidates to treat brain disorders. [ABSTRACT FROM AUTHOR]

Homology modeling emerges as a potent tool unveiling the structural enigma of intrinsically disordered proteins (IDPs), with recent advancements such as AlphaFold2 enhancing the precision of these analyses. The process usually involves identifying homologous proteins with known structures and utilizing their templates to predict the three-dimensional architecture of the target IDP. However, IDPs lack a well-defined three-dimensional structure, and their flexibility makes it difficult to predict their conformations accurately. On the other hand, special sampling molecular dynamics simulations have been shown to be useful in defining the distinct structural properties of IDPs. Here, the structural properties of the disordered amyloid-β42 peptide were predicted using various homology modeling tools, including C-I-TASSER, I-TASSER, Phyre2, SwissModel, and AlphaFold2. In parallel, extensive replica exchange molecular dynamics simulations of Aβ42 were conducted. Results from homology modeling were compared to our replica exchange molecular dynamics simulations and experiments to gain insights into the accuracy of homology modeling tools for IDPs used in this work. Based on our findings, none of the homology modeling tools used in this work can fully capture the structural properties of Aβ42. However, C-I-TASSER yields a radius of gyration and tertiary structure properties that are more in accord with the simulations and experimental data rather than I-TASSER, Phyre2, SwissModel, and AlphaFold2. [ABSTRACT FROM AUTHOR]

Background. Recombinant plasminogen activator (r-PA) consists of the Kringle-2 and protease domains of human tissue-type plasminogen. It is used clinically to treat coronary artery thrombosis and acute myocardial infarction. However, the expression and production of reteplase (r-PA) are limited due to its susceptibility to proteolysis during manufacturing processes. Therefore, efforts have been made to address this limitation. Materials and methods. To enhance the conformational stability of r-PA and increase its resistance to proteolysis, we used Gly 6 Ala substitutions in the Kringle-2 domain through in silico. We created an in silico mutant collection with eight structures, incorporating four designated mutations (R103S, G39A, G53A, and G55A). Using MODELLER software and homology modeling, we developed three-dimensional structures for two Kringle-2 and tissue plasminogen activator protease domains, including the wild noncleavable form (R103S) and mutants with all four designated mutations. We assessed protein stability using a dynamic cross-correlation matrix by extracting global properties such as Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) from trajectory files. Results. The findings revealed that a single glycine--alanine substitution (G39A) enhanced the conformational stability of r-PA, as evidenced by improvements in RMSD, RMSF, radius of gyration, surface accessibility, hydrogen bond formation, eigenvector projection, and density analysis. Conclusion. The conformational stability of r-PA conferred by glycine replacement with alanine may decrease the propensity for proteolysis in protease -- rich environments across various recombinant systems and potentially enhance its production and expression levels. [ABSTRACT FROM AUTHOR]

Methionine oxidation can substantially alter the structure and functionality of monoclonal antibodies (mAbs), especially when it occurs in the complementarity-determining regions (CDRs). It is imperative to fully understand the effects of methionine oxidation because these modifications can affect the binding affinity, stability, and immunogenicity of mAbs. Moreover, the presence of multiple methionines in close proximity within the amino acid sequence increases the complexity of accurate characterization, and sophisticated analytical methods are required to detect these modifications. In this study, we used hydrogen deuterium exchange mass spectrometry (HDX-MS) and homology modeling to investigate the effects of dual methionine oxidations (heavy chain (HC) Met111 and Met115) within a single CDR on the structure of a mAb. Our findings reveal that the solvent-accessible methionine (HC Met111) is more prone to oxidation, but such a modification does not result in conformational changes in the mAb. In contrast, the methionine (HC Met115) at the VH-VL interface, when subjected to different oxidative stresses, can undergo oxidation with selective stereochemistry. This can lead to predominant formation of either the S- or R-form of methionine sulfoxide diastereomer, each of which can induce distinct local conformational changes. A mechanism is proposed to elucidate these observations in this particular antibody. Furthermore, binding assays confirm that both CDR methionine oxidations do not compromise antigen binding, which alleviates concerns about potential loss of therapeutic efficacy.

The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.

IntroductionHomology modeling is a widely used computational technique for predicting the three-dimensional (3D) structures of proteins based on known templates,evolutionary relationships to provide structural insights critical for understanding protein function, interactions, and potential therapeutic targets. However, existing tools often require significant expertise and computational resources, presenting a barrier for many researchers.MethodsProstruc is a Python-based homology modeling tool designed to simplify protein structure prediction through an intuitive, automated pipeline. Integrating Biopython for sequence alignment, BLAST for template identification, and ProMod3 for structure generation, Prostruc streamlines complex workflows into a user-friendly interface. The tool enables researchers to input protein sequences, identify homologous templates from databases such as the Protein Data Bank (PDB), and generate high-quality 3D structures with minimal computational expertise. Prostruc implements a two-stage vSquarealidation process: first, it uses TM-align for structural comparison, assessing Root Mean Deviations (RMSD) and TM scores against reference models. Second, it evaluates model quality via QMEANDisCo to ensure high accuracy.ResultsThe top five models are selected based on these metrics and provided to the user. Prostruc stands out by offering scalability, flexibility, and ease of use. It is accessible via a cloud-based web interface or as a Python package for local use, ensuring adaptability across research environments. Benchmarking against existing tools like SWISS-MODEL,I-TASSER and Phyre2 demonstrates Prostruc's competitive performance in terms of structural accuracy and job runtime, while its open-source nature encourages community-driven innovation.DiscussionProstruc is positioned as a significant advancement in homology modeling, making high-quality protein structure prediction more accessible to the scientific community.

Cannabis sativa is an economically important crop, yet weed management remains a significant challenge due to limited herbicide options. Cytochrome P450 enzymes play crucial roles in plant metabolism, including herbicide detoxification. This study aimed to identify and characterize the CYP gene family in Cannabis and investigate their potential role in herbicide metabolism. We identified 225 CYP proteins encoded by 221 genes in the Cannabis genome, classified into 9 clans and 47 families. The majority of CsCYPs were predicted to be located in endomembrane system and chromosomal mapping revealed that they were present in all the chromosomes. Motif and gene structure analysis supported the results from phylogenetic analysis. The gene duplication analysis results showed that tandem duplication plays a pivotal role in evolutionary expansion of CsCYP superfamily. Promoter analysis revealed various cis-acting elements involved in stress, light, hormone and development responses. Molecular docking simulations identified several CsCYPs with strong binding affinities to ALS-inhibiting herbicides, particularly bispyribac-sodium, propoxycarbazone-sodium, and pyriftalid. CsCYP_215, CsCYP_213, CsCYP_217 and CsCYP_14 emerged as promising candidates for herbicide metabolism. Analysis of binding site residues revealed the importance of hydrophobic and aromatic interactions in herbicide binding. This study provides the first comprehensive characterization of the CYP gene family in C. sativa and offers new insights into their potential roles in herbicide metabolism. The identification of promising herbicide-metabolizing CYP candidates opens new avenues for developing herbicide-tolerant Cannabis varieties, potentially addressing key challenges in weed management and crop productivity.

الملخص: أهداف البحث: تم تصميم هذا العمل لدراسة 4،2-مزدوج الاستبدال 6-فلوروكينولين كعوامل مضادة للبلازموديات تستخدم في تقنيات السيليكو بهدف الكشف عن المعلومات التي يمكن استخدامها لتصميم نظائر جديدة ذات فاعلية عالية كمضاد للملاريا وقدرة تثبيط عالية تجاه عامل تطويل الترجمة2 لـ المتصورة المنجلية، هدف دوائي جديد. طريقة البحث: تمت دراسة العلاقة الكمية بين البنية والنشاط لـ 4،2-مزدوج الاستبدال 6-فلوروكينولين باستخدام تقنية تقريب الوظيفة الجينية في برنامج استديو الأدوات. تم تصميم البنية ثلاثية الأبعاد لـ عامل تطويل الترجمة2 لـ المتصورة المنجلية من مساحة عمل النموذج السويسري استنادا إلى تقنية النمذجة المتماثلة. أجريت دراسة الالتحام الجزيئي ل عامل تطويل الترجمة2 النموذجي 4،2-مزدوج الاستبدال 6-فلوروكينولين غير المستبدل باستخدام ''أوتودوك فينا'' في برنامج ''بايركس''. علاوة على ذلك، تم دراسة الخصائص الدوائية لبعض المركبات المختارة في السيليكو. النتائج: طور هذا البحث نموذجا قويا وموثوقا وتنبؤيا للعلاقة بين البنية والنشاط الكمي الذي يربط التركيبات الكيميائية لـ 4،2-مزدوج الاستبدال 6-فلوروكينولين مع أنشطتها المضادة للبلازموديوم. يحتوي النموذج على معامل الارتباط التربيعي الداخلي، ''آر2'' بقيمة 0.921، ومعامل الارتباط المربع المعدل، ''آر2أدج'' بقيمة 0.878، ومعامل التحقق من صحة الإجازة الواحدة، ''كيو2سي في'' بقيمة 0.801 ومعامل الارتباط التربيعي التنبؤي، ''آر2بريد'' بقيمة 0.901. يوضح أن الأنشطة المضادة للبلازموديوم لـ 6-فلوروكينولين تعتمد على الخواص الفيزيائية والكيميائية لـ ''حلقة5ان''، ''جي جي آي 9''، ''تي دي بي 7 يو''، ''تي دي بي 8 يو''، ''آر دي اف 75 آي'' مساهمة إيجابية بينما يكون لـ ''جي جي آي 9'' و ''تي دي بي 7 يو'' مساهمة سلبية في الأنشطة المضادة للبلازموديوم للمركبات. تم تشكيل مجمعات مستقرة بين المركبات ونموذج عامل تطويل الترجمة2 لـ المتصورة المنجلية مع تقارب ربط يتراوح من -8.200 إلى -10.700 كيلو كالوري/مول. يحتوي المركب 5 و11 و16 و22 و24 على ارتباطات ربط أفضل من الكينولين-4-كربوكساميد ويظهر خصائص حركية دوائية جيدة، وبالتالي يمكن أن يكون مثبطا أفضل لهذا الهدف الجديد.الاستنتاجات: يمكن للمعلومات التي كشفت عنها العلاقة الكمية بين البنية والنشاط ودراسات الالتحام للمركبات أن تعطي نظرة ثاقبة لطريقة تصميم 4،2-مزدوج الاستبدال 6-فلوروكينولين مع أنشطة مضادة للبلازموديات عالية وخصائص هيكلية جيدة لتثبيط هدف الدواء المضاد للملاريا الجديد. Abstract: Objective: This work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target. Methods: Quantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated. Results: A robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from −8.200 to −10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target. Conclusion: QSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.

Computer-aided design usually gives inspirations and has become a vital strategy to develop novel pesticides through reconstructing natural lead compounds. Patulin, an unsaturated heterocyclic lactone mycotoxin, is a new natural PSII inhibitor and shows significant herbicidal activity to various weeds. However, some evidence, especially the health concern, prevents it from developing as a bioherbicide. In this work, molecular docking and toxicity risk prediction are combined to construct interaction models between the ligand and acceptor, and design and screen novel derivatives. Based on the analysis of a constructed patulin–Arabidopsis D1 protein docking model, in total, 81 derivatives are designed and ranked according to quantitative estimates of drug-likeness (QED) values and free energies. Among the newly designed derivatives, forty-five derivatives with better affinities than patulin are screened to further evaluate their toxicology. Finally, it is indicated that four patulin derivatives, D3, D6, D34, and D67, with higher binding affinity but lower toxicity than patulin have a great potential to develop as new herbicides with improved potency. [ABSTRACT FROM AUTHOR]

Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug resistance, increased toxicities, and impoverished pharmacokinetic profiles exhibited by conventional drugs have hindered the search for new entities. Plasmepsins, a group of Plasmodium-specific, aspartic acid protease enzymes, are involved in many key aspects of parasite biology, and this makes them interesting targets for antimalarial chemotherapy. Among different isoforms, PlmIX serves as an unexplored antimalarial drug target that plays a crucial role along with PlmV and X in the parasite's survival by digesting hemoglobin in the host's erythrocytes. In this study, fragment-based virtual screening was performed by modeling the three-dimensional structure of PlmIX and predicting its ligand-binding pocket by using the Sitemap tool. Screening identified the fragments with the XP docking score ≤ -3 kcal/mol from the OTAVA General Fragment Library (≈16,397 fragments), and the selected fragments were chosen for ligand breeding. The resulting ligands (≈69,858 ligands) were subsequently subjected to filtering based on the QikProp properties along with carcinogenicity testing performed using CarcinoPred-EL and then docked in the SP (≈14,078 ligands) as well as XP mode (≈3,104 ligands), and compared with that of control ligands 49C and I0L. The top-ranked ligands were taken further for the calculation of the free energy of binding using Prime MM--GBSA. Overall, a total of six complexes were taken further for MD simulation studies performed at 100 ns to attain a better understanding of the binding mechanisms, and compounds 3 and 4 were found to be the most efficient ones in silico. The analysis of compound 3 revealed that the carbonyl group present in position 1 on the isoindoline moiety (Arg554) was responsible for inhibitory activity against PlmIX. However, the analysis of compound 4 revealed that the amide linkage sandwiched between the phenyl ring and isoquinoline moiety (Lys555 and Ser226) as well as carbonyl oxygen of the carbamoyl group present at position 2 of the pyrazole ring (Gln222) were responsible for PlmIX inhibitory activity, owing to their crucial interactions with key amino acid residues. [ABSTRACT FROM AUTHOR]

Cotton leaf curl Multan virus (CLCuMuV), is a begomovirus encoding a protein, Replication associated protein (Rep) infect cotton crop. If the function of this protein is disrupted virus fails to replicate and subsequently cannot complete its life cycle. In this study plant-based chemicals were tested as inhibitors of Rep protein of CLCuMuV. In this study, sequence and docking analysis, calculations of physicochemical parameters and three-dimensional structural modeling of Rep protein of CLCuMuV against selected phytochemicals were performed. Based on docking analysis the best phytochemicals were reported. Analysis of the sequence and physicochemical properties revealed the Rep protein as negatively charged, slightly acidic, and prone to instability. The three-dimensional model of the protein showed that it consists of two helices, nine beta-pleated sheets, and eleven coiled regions. More than 900 phytochemicals were used in the docking experiment. Ten phytochemicals were obtained as potential inhibitors of Rep protein based on docking score. Through the analysis of the interaction, the atoms that participate in each interaction between the Rep protein and phytochemicals were identified. The results indicated that phytochemicals are potential inhibitors of Rep protein of CLCuMuV. Our study will be useful for devising resistance strategies against CLCuMuV in cotton. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants that impart several hazardous effects on the environment. Extracellular enzymes released by filamentous fungi are well-known participants in the degradation of such organic pollutants. The present study aims to determine the interaction of pyrene with Lac1 protein, coding for the extracellular laccase enzyme from Trichoderma sp. CNSC-2. Lac1 sequence analysis revealed the stable and acidic nature of the laccase enzyme. The dominance of random coils (54.8%) and extended strands (28.3%) in secondary structure defined protein flexibility. 3D homology modeling followed by validation revealed a high-quality model with 94.8% residues in the favored zone of Ramachandran plot. Molecular docking study with pyrene displayed a significant binding affinity of −7.82 kcal mol−1 with the amino acid residues at the active binding site of Lac1, indicating a strong role in pyrene binding. Trichoderma sp. CNSC-2 achieved 69.42 ± 0.4% of pyrene removal efficiency at 100 mg l−1 pyrene concentration on day 12 of incubation. Laccase activity during pyrene degradation simultaneously increased, and the highest activity was observed on day 6 of incubation. Enzyme production was found to be optimum at pH 6 (p < 0.001) and 30°C temperature (p < 0.0001). FTIR analysis showed deviation in the amide bands of laccase in the presence of pyrene, and additional peaks coinciding with pyrene metabolites were observed. The decrease in intensity of laccase due to quenching by pyrene interaction was determined by fluorescence spectroscopy. Thus, this study suggested a strong binding affinity of pyrene to the laccase active site implying the potential role of laccase enzyme from Trichoderma sp. CNSC-2 in pyrene degradation. [ABSTRACT FROM AUTHOR]

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The distinctive morphology characteristics of microfold cells (M cells) allow the vaccine antigen not only to interact with immune cells directly, but also to effectively stimulate mucosal immune responses via receptors on its apical surface. Human prion protein, a transmembrane receptor for Brucella abortus Hsp60, is highly expressed on the M cell surface. Nonetheless, this protein tends to express in inclusion body in prokaryotic hosts. In this study, the shorter interacting regions of human prion protein were identified via computational methods such as docking and molecular dynamics simulations to minimize its aggregation tendency. The computational calculations revealed three novel human prion protein-interacting regions, namely PrP125, PrP174, and PrP180. In accordance with in silico prediction, the biologically synthesized peptides fusing with GST tag demonstrated their specific binding to Hsp60 protein via pull-down assay. Hence, this finding laid the groundwork for M-cell targeting candidate validation through these newly identified interacting regions. [ABSTRACT FROM AUTHOR]

Ebola virus disease is a deadly pathogenic disease with a fatality rate of 25–90 % as recorded in previous outbreaks. The Ebola Virus glycoprotein (EBOV-GP) plays a crucial role in the entry of viruses into human cells, making it an interesting target for therapeutic discovery. Therefore, inhibiting this protein can directly limit the virus replication and disease progression at an early stage of infection. The present study focuses on the design of novel potent EBOV-GP inhibitors using multiple computational techniques. In this context, two QSAR models were built from a set of 86 amodiaquine derivatives as anti-EBOV-GP using Monte Carlo and genetic algorithm multiple linear regression methods. Both models confirmed their predictive performance with satisfactory statistical parameters of the validation (R2 = 0.9129; Q2 = 0.8848 for the CORAL model and R2 = 0.8848; Q2 = 0.8148 for the GA-MLR model). From the outputs of the CORAL model, the structural fragments responsible for increasing and decreasing the inhibition activity were extracted and interpreted. This molecular information was used to design 26 new potentially safe and active candidate drugs. Molecular docking and dynamics simulations have affirmed the efficacy of the designed compounds. Specifically, compounds D2 (pIC50_coral = 7.12; pIC50_GA-MLR = 7.07), D3 (pIC50_coral = 7.83; pIC50_GA-MLR = 7.10), and D5 (pIC50_coral = 7.26; pIC50_GA-MLR = 7.55) displayed notable predicted inhibitory activity, according to both models. These compounds also exhibited conformational and structural stability, as well as a favorable binding profile. Furthermore, these potential drug candidates were found to be non-toxicity and have acceptable pharmacological properties.

Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease that leads to reduced saliva production, primarily affecting women due to estrogen deficiency. The estrogen receptor α (ERα) plays a crucial role in mediating the expression of the aquaporin 5 (AQP5) gene through the estrogen response element-dependent signaling pathway, making ERα a key drug target for pSS. Several flavonoids have been reported to have the potential to treat pSS. This study aimed to screen and compare flavonoids binding to ERα using AutoDock, providing a basis for treating pSS with flavonoids. The estrogenic potential of six representative flavonoids was examined in this study. Molecular docking revealed that the binding energy of all six flavonoids to ERα was less than −5.6 kcal/mol. Apigenin, naringenin, and daidzein were the top three flavonoids with even lower binding energies of −7.8, −8.09, and −8.59 kcal/mol, respectively. Similar to the positive control estradiol, apigenin, naringenin, and daidzein showed hydrogen bond interactions with GLU353, GLY521, and HIS524 at the active site. The results of luciferase reporter assays demonstrated that apigenin, naringenin, and daidzein significantly enhanced the transcription of estrogen receptor element (ERE) in the PGL3/AQP5 promoter. Furthermore, molecular dynamics simulations using GROMACS for a time scale of 100 ns revealed relatively stable binding of apigenin-ERα, naringenin-ERα, and daidzein-ERα. Mechanistically, homology modeling indicated that GLU353, GLY521, and HIS524 were the key residues of ERα exerting an estrogenic effect. The therapeutic effect of apigenin on dry mouth in pSS models was further validated. In conclusion, these results indicate the estrogenic and pSS therapeutic potential of apigenin, naringenin, and daidzein.

Abstract This is the first report on the screening, expression, and recognition mechanism analysis of single-chain fragment variable (scFv) against phenylethanolamine A (PEAA), a newly emerged β-adrenergic agonist illegally used as a feed additive for growth promotion. The PEAA-specific scFv scFv, called scFv-32, was screened from hybridoma cell lines by phage display and was found to be optimally expressed in the E. coli system. The ic-ELISA results revealed an IC50 value of 10.34 μg/L for scFv-32 and no cross-reactivity with other β-adrenergic agonists. Homology modeling and molecular docking revealed the key binding sites VAL178, TYP228, and ASP229. One hydrogen bond, two pi-sigma bonds, and one pi-pi bond maintain the formation of the antibody‒drug complex. Alanine scanning mutagenesis of the three predicted key binding sites showed that the mutants completely lost their recognition activity, which confirmed the accuracy of the theoretical analysis. These results are valuable for the preparation of scFvs and the analysis of the molecular recognition mechanism of antigen-antibodies. Graphical abstract

Abstract Anti-cancer peptides (ACPs) are short peptides known for their ability to inhibit tumor cell proliferation, migration, and the formation of tumor blood vessels. In this study, we designed ACPs to target receptors often overexpressed in cancer using a systematic in silico approach. Three target receptors (CXCR1, DcR3, and OPG) were selected for their significant roles in cancer pathogenesis and tumor cell proliferation. Our peptide design strategy involved identifying interacting residues (IR) of these receptors, with their natural ligands serving as a reference for designing peptides specific to each receptor. The natural ligands of these receptors, including IL8 for CXCR1, TL1A for DcR3, and RANKL for OPG, were identified from the literature. Using the identified interacting residues (IR), we generated a peptide library through simple permutation and predicted the structure of each peptide. All peptides were analyzed using the web-based prediction server for Anticancer peptides, AntiCP. Docking simulations were then conducted to analyze the binding efficiencies of peptides with their respective target receptors, using VEGA ZZ and Chimera for interaction analysis. Our analysis identified HPKFIKELR as the interacting residues (IR) of CXCR-IL8. For DcR3, we utilized three domains from TL1A (TDSYPEP, TKEDKTF, LGLAFTK) as templates, along with two regions (SIKIPSS and PDQDATYP) from RANKL, to generate a library of peptide analogs. Subsequently, peptides for each receptor were shortlisted based on their predicted anticancer properties as determined by AntiCP and were subjected to docking analysis. After docking, peptides that exhibited the least binding energy were further analyzed for their detailed interaction with their respective receptors. Among these, peptides C9 (HPKFELY) and C7 (HPKFEWL) for CXCR1, peptides D6 (ADSYPQP) and D18 (AFSYPFP) for DcR3, and peptides P19 (PDTYPQDP) and p16 (PDQDATYP) for OPG, demonstrated the highest affinity and stronger interactions compared to the other peptides. Although in silico predictions indicated a favorable binding affinity of the designed peptides with target receptors, further experimental validation is essential to confirm their binding affinity, stability and pharmacokinetic characteristics.

Objective To explore the interactive protein and mode of oncogene alkylglycerone phosphate synthase (AGPS) in glioma U251 cells. Methods U251 cells were routinely cultured and divided into the control group, shRAGPS-1 group and shR-AGPS-2 group, respectively, which were added with the negative control lentivirus and AGPS shRNA lentiviruse with different silencing levels. Western blotting was used to detect the expression of AGPS protein to verify the silencing efficiency. The interactive protein of AGPS was identified by immunoprecipitation and mass spectrometry, and was identified by Western blotting. The homologous modeling of the interactive proteins of AGPS was established by computer simulation and the interaction mode was predicted. Results Compared with the control group, the expression of AGPS decreased in the shR-AGPS-1 group and shR-AGPS-2 group and the expression of AGPS was lower in the shRAGPS-1 than in the shR-AGPS-2 group (all P<0. 05). It was predicted that heterogeneous nuclear ribonucleoprotein K (HNRNPK) was the target protein of AGPS, and both AGPS and HNRNPK were detected in the AGPS immunoprecipitation lysate, which indicated that AGPS and HNRNPK formed complexes, and both of them were expressed in the nucleus. The results of computer simulation showed that AGPS and HNRNPK were interacted through amino acid residues based on hydrogen bond, conjugation, hydrophobic bond and electrostatic force. Conclusion The HNRNPK is the interactive protein of AGPS in glioma, and the interaction of hydrogen bond, conjugation, hydrophobic bond and electrostatic force may be the main modes of action of AGPS. [ABSTRACT FROM AUTHOR]

Empirically, in Indonesia, the leaves of Cassia alata L. (candle bush or ketepeng cina) have been used as a topical antifungal agent. Malassezia furfur is a natural microorganism found in the human body. It is among the factors contributing to conditions such as pityriasis versicolor, a common, benign, superficial fungal infection of the skin that is closely associated with seborrheic dermatitis and dandruff. This study aimed to explore C. alata leaves, starting from determining antifungal activity against M. furfur and the identification of major compounds in the ethyl acetate and n-hexane fractions, and then we carried out molecular docking of the major compounds in the n-hexane fraction to lanosterol 14-alpha demethylase. The method was the disc diffusion technique to test antifungal activity, LC-MS/MS for major compound identification, and homology modeling through Swiss Models for molecular docking. The fractions of ethyl acetate and n-hexane extract showed concentration-dependent antifungal activity against M. furfur. The LCMS/MS analysis revealed five major compounds in the ethyl acetate and n-hexane fractions. The molecular docking demonstrated the highest binding affinity with stearidonic acid at −7.2 kcal/mol. It can be concluded that the compounds in the n-hexane fraction have antifungal activity against M. furfur, as supported by both in vitro and in silico studies. [ABSTRACT FROM AUTHOR]

Bioinformatics resolves biological problems by predicting the structural-functional annotation of genes and substantially contributes to further downstream applications in the field of genomics. Most of the proteins from Colletotrichum gloeosporoides are uncharacterized yet, which could be of novel biological functions and help to understand the biological function. Hence, in this study, we aimed to annotate the zinc-finger dhhc domain containing uncharacterized protein A0A8H4C4Q8_COLGL of C. gloeosporoides. The uncharacterized protein was analyzed for subcellular localization, physicochemical characteristics, secretory nature, antigenicity, allergenicity determination, conserved domain identification, secondary structure prediction, 3D modeling, docking analysis, active site prediction, and protein-protein interaction. The structural-functional annotation predicted it as an effector protein possessing a role in pathogenicity. [ABSTRACT FROM AUTHOR]

In our continuous effort to develop novel antiepileptic drug, a new series of nipecotic acid derivatives having1,3,4-thiadiazole nucleus were designed and synthesized. This study aims to improve the lipophilicity of nipecotic acid by attaching some lipophilic anchors like thiadiazole and substituted aryl acid derivatives. In our previous study, we noticed that the N-substituted oxadiazole derivative of nipecotic acid exhibited significant antiepileptic activity in the rodent model. The synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, Mass, and elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock-induced seizure model in rats (MES) and the subcutaneous pentylenetetrazol (scPTZ) test in mice. None of the compounds were found to be active in the MES model whereas compounds (TN2, TN9, TN12, TN13, and TN15) produced significant protection against the scPTZ-induced seizures model. The compounds showing antiepileptic activity were additionally evaluated for antidepressant activity by using the forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitch test, and learned helplessness test. All the molecules that showed anticonvulsant activity (TN2, TN9, TN12, TN13, and TN15), also exerted significant antidepressant effects in the animal models. The selected compounds were subjected to different toxicity studies. Compounds were found to have no neurotoxicity in the rota-rod test and devoid of hepatic and renal toxicity in 30 days repeated oral toxicity test. Further, a homology model was developed to perform the in-silico molecular docking and dynamics studies which revealed the similar binding of compound TN9 within the active binding pocket and were found to be the most potent anti-epileptic agent. The market expectation for newly developed antiepileptic thiadiazole-based nipecotic acid derivatives is significant, driven by their potential to offer improved therapeutic outcomes and reduced side effects, addressing a critical need in epilepsy treatment. These innovative compounds hold promise for meeting the demand for more effective and safer antiepileptic medications. [ABSTRACT FROM AUTHOR]

Background: The present study investigates the interrelated pathophysiology of depression and Alzheimer's disease (AD), with the objective of elucidating common underlying mechanisms. Objective: Our objective is to identify previously undiscovered biogenic compounds from the NuBBE database that specifically interact with GluR3. This study examines the bidirectional association between depression and AD, specifically focusing on the role of depression as a risk factor in the onset and progression of the disease. Methods: In this study, we utilize pharmacokinetics, homology modeling, and molecular docking-based virtual screening techniques to examine the GluR3 AMPA receptor subunit. Results: The compounds, namely ZINC000002558953, ZINC000001228056, ZINC000000187911, ZINC000003954487, and ZINC000002040988, exhibited favorable pharmacokinetic profiles and drug-like characteristics, displaying high binding affinities to the GluR3 binding pocket. Conclusions: These findings suggest that targeting GluR3 could hold promise for the development of therapies for depression and AD. Further validation through in vitro, in vivo, and clinical studies is necessary to explore the potential of these compounds as lead candidates for potent and selective GluR3 inhibitors. The shared molecular mechanisms between depression and AD provide an opportunity for novel treatment approaches that address both conditions simultaneously. [ABSTRACT FROM AUTHOR]

Neurokinin/tachykinin receptors are classified as the G‐protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three‐dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand–NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets. [ABSTRACT FROM AUTHOR]

Microbial lipases are utilized in various biotechnological areas, including pharmaceuticals, food, biodiesel, and detergents. In this study, we cloned and sequenced Lip21 and Lip33 genes from Geobacillus sp. GS21 and Geobacillus sp. GS33, then we in silico and experimentally analyzed the encoded lipases. For this purpose, Lip21 and Lip33 were cloned, sequenced, and their amino acid sequences were investigated for determination of biophysicochemical characteristics, evolutionary relationships, and sequence similarities. 3D models were built and computationally affirmed by various bioinformatics tools, and enzyme‐ligand interactions were investigated by docking analysis using six ligands. Biophysicochemical property of Lip21 and Lip33 was also determined experimentally and the results demonstrated that they had similar isoelectric point (pI) (6.21) and Tm (75.5°C) values as Tm was revealed by denatured protein analysis of the circular dichroism spectrum and pI was obtained by isoelectric focusing. Phylogeny analysis indicated that Lip21 and Lip33 were the closest to lipases from Geobacillus sp. SBS‐4S and Geobacillus thermoleovorans, respectively. Alignment analysis demonstrated that S144–D348–H389 was catalytic triad residues in Lip21 and Lip33, and enzymes possessed a conserved Gly‐X‐Ser‐X‐Gly motif containing catalytic serine. 3D structure analysis indicated that Lip21 and Lip33 highly resembled each other and they were α/β hydrolase‐fold enzymes with large lid domains. BANΔIT analysis results showed that Lip21 and Lip33 had higher thermal stability, compared to other thermostable Geobacillus lipases. Docking results revealed that Lip21‐ and Lip33‐docked complexes possessed common residues (H112, K115, Q162, E163, and S141) that interacted with the substrates, except paranitrophenyl (pNP)‐C10 and pNP‐C12, indicating that these residues might have a significant action on medium and short‐chain fatty acid esters. Thus, Lip21 and Lip33 can be potential candidates for different industrial applications. [ABSTRACT FROM AUTHOR]

Recent research has uncovered a promising approach to addressing the growing global health concern of obesity and related disorders. The inhibition of inositol hexakisphosphate kinase 1 (IP6K1) has emerged as a potential therapeutic strategy. This study employs multiple ligand-based in silico modeling techniques to investigate the structural requirements for benzisoxazole derivatives as IP6K1 inhibitors. Firstly, we developed linear 2D Quantitative Structure–Activity Relationship (2D-QSAR) models to ensure both their mechanistic interpretability and predictive accuracy. Then, ligand-based pharmacophore modeling was performed to identify the essential features responsible for the compounds' high activity. To gain insights into the 3D requirements for enhanced potency against the IP6K1 enzyme, we employed multiple alignment techniques to set up 3D-QSAR models. Given the absence of an available X-ray crystal structure for IP6K1, a reliable homology model for the enzyme was developed and structurally validated in order to perform structure-based analyses on the selected dataset compounds. Finally, molecular dynamic simulations, using the docked poses of these compounds, provided further insights. Our findings consistently supported the mechanistic interpretations derived from both ligand-based and structure-based analyses. This study offers valuable guidance on the design of novel IP6K1 inhibitors. Importantly, our work exclusively relies on non-commercial software packages, ensuring accessibility for reproducing the reported models. [ABSTRACT FROM AUTHOR]

Computer modeling and protein structure visualization tools are effective and engaging ways of presenting various molecular biology concepts to high school and college students. Here, we describe a series of activities and exercises that use online bioinformatics databases and programs to search for and obtain protein sequence and structure data and use it to build homology models of proteins. Exercises in homology modeling can serve the pedagogical purpose of introducing and illustrating the concept of homology within gene and protein families, which results in conservation of the 3D structures of proteins and allows us to predict structures when experimental data are not available. [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV). HIV protease, reverse transcriptase, and integrase are targets of current drugs to treat the disease. However, anti-viral drug-resistant strains have emerged quickly due to the high mutation rate of the virus, leading to the demand for the development of new drugs. One attractive target is Gag-Pol polyprotein, which plays a key role in the life cycle of HIV. Recently, we found that a combination of M50I and V151I mutations in HIV-1 integrase can suppress virus release and inhibit the initiation of Gag-Pol autoprocessing and maturation without interfering with the dimerization of Gag-Pol. Additional mutations in integrase or RNase H domain in reverse transcriptase can compensate for the defect. However, the molecular mechanism is unknown. There is no tertiary structure of the full-length HIV-1 Pol protein available for further study. Therefore, we developed a workflow to predict the tertiary structure of HIV-1 NL4.3 Pol polyprotein. The modeled structure has comparable quality compared with the recently published partial HIV-1 Pol structure (PDB ID: 7SJX). Our HIV-1 NL4.3 Pol dimer model is the first full-length Pol tertiary structure. It can provide a structural platform for studying the autoprocessing mechanism of HIV-1 Pol and for developing new potent drugs. Moreover, the workflow can be used to predict other large protein structures that cannot be resolved via conventional experimental methods. [ABSTRACT FROM AUTHOR]