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In the present study, a novel series of sulfamethoxazole and 1-(2-fluorophenyl) piperazine derivatives were designed, synthesized and characterized by FTIR, I H NMR, 13 C NMR, Mass spectrometry, CHN data, and evaluated for their efficiency as BCL2 inhibitors that could lead to potential antiproliferative activity. The ten newly synthesized compounds were screened for their therapeutic activity using MDA-MB-231 breast cancer cell lines. All the test compounds exhibited moderate to high cytotoxic activity in MTT assay. Among them, compounds 3e and 6b exhibited promising antitumor activity, as evidenced by their IC 50 values of 16.98 and 17.33 μM respectively. In addition, both compounds 3e and 6b displayed potential antioxidant and apoptosis induction properties. The qRT-PCR analysis showed down regulation of BCL2 expression and up regulation of Casp3 expression in 3e and 6b treated MDA-MB-231 cells. Further, the interaction between critical amino acids of the active domains of BCL2 and 3e and 6b was evaluated by MD simulation, and the results reflected the potent inhibitory activities of 3e and 6b . In summary, the novel compounds 3e and 6b demonstrate their potent anti-cancer properties by inducing apoptosis and selectively targeting BCL2 and caspases-3., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04111-6., Competing Interests: Conflict of interestThere are no competing financial interests declaredby the authors., (© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine., (© 2024. The Author(s).)

The heat shock protein 90 kDa (Hsp90) chaperone machinery plays a crucial role in maintaining cellular homeostasis. Beyond its traditional role in protein folding, Hsp90 is integral to key pathways influencing cellular function in health and disease. Hsp90 operates through the modular assembly of large multiprotein complexes, with their composition, stability, and localization adapting to the cell's needs. Its functional dynamics are finely tuned by ligand binding and post-translational modifications (PTMs). Here, we discuss how to disentangle the intricacies of the complex code that governs the crosstalk between dynamics, binding, PTMs, and the functions of the Hsp90 machinery using computer-based approaches. Specifically, we outline the contributions of computational and theoretical methods to the understanding of Hsp90 functions, ranging from providing atomic-level insights into its dynamics to clarifying the mechanisms of interactions with protein clients, cochaperones, and ligands. The knowledge generated in this framework can be actionable for the design and development of chemical tools and drugs targeting Hsp90 in specific disease-associated cellular contexts. Finally, we provide our perspective on how computation can be integrated into the study of the fine-tuning of functions in the highly complex Hsp90 landscape, complementing experimental methods for a comprehensive understanding of this important chaperone system., Competing Interests: Declarations of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes-namely, protein assemblies-under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation's influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.

Epithelial-mesenchymal transition (EMT) is a vital process in tumorigenesis and metastasis of breast cancer. In our quest to explore effective anticancer alternatives, ursolic acid (UA) was purified from Capparis zeylanica and investigated for its anticancer activity against MDA-MB-231 and MCF-7 breast cancer cells. The apparent anticancer activity of UA on MDA-MB-231 and MCF-7 cells was evident from IC50 values of 14.98 and 15.99 μg/mL, respectively, in MTT assay and also through enhanced generation of ROS. When MDA-MB-231 and MCF-7 cells were treated with 20 μg/mL UA, an absolute decrease in cell viability of 47.6% and 48.6%, enhancement of 1.35% and 1.10% in early apoptosis, and 21.90% and 21.35% in late apoptosis, respectively and G 0 /G 1 phase, S phase, G 2 /M phase cell cycle arrest was noticed. The gene expression studies revealed that UA could significantly (p < 0.001) downregulate the expression of EMT markers such as snail, slug, and fibronectin at molecular level. Further, the obtained in vitro results of snail, slug, and fibronectin were subjected to quantum-polarized-ligand (QM/MM) docking, which predicted that the in silico binding affinities of these three markers are in good correlation with strong hydrogen and van der Waal interactions to UA with -53.865, -48.971 and -40.617 MMGBSA (ΔG bind ) scores, respectively. The long-range molecular dynamics (50 ns) simulations have showed more consistency by UA. These findings conclude that UA inhibits breast cancer cells growth and proliferation through regulating the expression of key EMT marker genes, and thus UA is suggested as a potential anticancer agent., (© 2023 Wiley Periodicals LLC.)

The study deals with structure-based rational drug design against the chief zinc-rely endopeptidase called matrilysin (MMP-7) that is involved in inflammatory and metastasis process of several carcinomas. Hyperactivated matrilysin of human was targeted, because of its hydrolytic actions on extracellular matrix (ECM) protein components constitutes fibrillar collagens, gelatins, fibronectins and it also activates zymogen forms of vital matrix metalloproteinases (gelatinase A-MMP-2 and B-MMP-9) responsible for ECM destruction in many cancers. In the present work, e-pharmacophores were generated for the respective five co-crystal structures of human matrilysin by mapping ligand's pharmacophoric features. During the lead-optimization campaign, the five e-pharmacophores-based shape screening against an in-house library of >21 million compounds created a dataset of 5000 structural analogs. The subsequent three different docking strategies, including rigid-receptor docking, quantum-polarized-ligand docking, induced-fit docking and free energy binding calculations resulted four leads as novel and potent MMP-7 binders. These four leads were observed with good pharmacological features and good receiver operating characteristics curve metrics (ROC: 0.93) in post-docking evaluations against five existing co-crystal inhibitors and 1000 decoy molecules with MMP-7. Moreover, stability and dynamics behavior of matrilysin-lead1 complex and matrilysin-cocrystal ligand (TQJ) complex were analyzed in natural physiological milieu of 1000 ns or 1 µs molecular dynamics simulations. Lead1-MMP-7 complex was found with an average C α root-mean-square deviation (RMSD) of 2.35 Å, average ligand root-mean-square fluctuations (RMSF) of 0.66 Å and the strong metallic interactions with E220, a key residue for proteolytic action thereby hinders ECM proteolysis that in turn can halt metastatic cancerous condition.Communicated by Ramaswamy H. Sarma.

A series of novel substituted bisurea 1,4-Diisocyanatobenzene compounds were designed, synthesized and introduced as potent anticancer compounds and screened for their in vitro anti-proliferative activities in human cancer cell lines. The structures of all titled compounds were characterized using Fourier-transform infrared mass spectra, nuclear magnetic resonance spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. A selected group of ten derivatives were apprised for their anti-proliferative activity. The compounds 3d and 3e displayed potent anticancer activity with low IC 50 value of 5.40, and 5.89 μM against HeLa cancer cell lines. The observed apoptosis data has demonstrated that compounds 3d and 3e induce the activaties of caspase-9 and caspase-3, the compounds 3d and 3e regulated fungal zone inhibition. Due to promising growth inhibitions, the all synthesized compounds were allowed to campaign includes quantum-polarized-ligand, quantum mechanical and molecular mechanical, docking experiments. The compounds 3d and 3e have exhibited a higher affinity for ERK/MAP kinase and CDK2 proteins. The molecular docking interactions have demonstrated two stage inhibition of cancer cells by binding with ERK/MAP kinase and CDK2 leads to inactivation of cell proliferation,cell cycle progression,cell divisionanddifferentiation, and hypo-phosphorylation of ribosome leading cells to restricts at point boundary of the G1/S phase. The long-range molecular dynamics, 150 ns, simulations were also revealed more consistency by 3d. Our study conclude good binding propensity for active-tunnel of ERK/MAP kinase and CDK2 proteins, by 3d (1,1'-(1,4-phenylene) bis(3-(2-chlorobenzyl)urea)), to suggest that the designed and synthesized 3d is to use as selective novel nuclei in anti-cancer chemotherapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The objectives of the present work are to design, syhthesize and introduce novel urea/thiourea derivatives of 2-(piperazine-1-yl)-pyrimidine and 1-(4-Fluoro/4-Chloro phenyl)-piperazine molecules as tobacco mosaic virus (TMV) inhibitors. A series of urea/thiourea derivatives containing pyrimidine and piperazine moieties were synthesized, characterized using Fourier-transform infrared (FTIR) mass spectra, nuclear magnetic resonance (NMR) spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. The anti-viral bioassay of the title compounds showed an antiviral activity against TMV. The compounds synthesized, 9j, 6g and 3d, showed highly-potential curative, protective, and inhibitory activities against TMV at 500 mg/mL formulation. All these compounds were allowed to quantum-polarized-ligand (quantum mechanical and molecular mechanical (QM/MM)) docking experiments. The compounds 9j, 6g and 3d structurally exhibited identical higher affinity towards TMV-Helicase and TMV-Coat proteins. The docking interactions proposed had two stage inhibition of TMV virus by binding to coat protein and helicase for inhibition of RNA replication. The long-range molecular dynamics (150 ns) simulations has revealed more consistency by 9j, 6g and 3d. The present study outcomes good binding propensity for active-tunnel of TMV-Hel enzyme, by these thiourea, urea derivatives, 9j, 6g and 3d, to suggest that the designed and synthesized were ideal for proposing as selective novel inhibitors to target for TMV., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

An endless drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of H. pylori infections, thereby ambitious novel proof-of-concept for inhibitor design was practiced in advancement of medication. Dihydropteroate synthase (DHPS) is an alluring target that plays a great role in folate synthesis pathway essential for amino acids biosynthesis was selected for designing novel drugs to prevent infections caused by pathogenic H. pylori . In the present study, a reliable tertiary structure of DHPS in complex with inhibitor 6MB was constructed by Modeler 9v19. DrugBank compounds of DHPS, published inhibitors, and co-crystal ligand (6MB) were docked against DHPS. The best docked compounds were screened against 28.5 million compounds resulted 1186 structural analogs. Virtual screening workflow and quantum polarized ligand dockings of these compounds against DHPS resulted three leads that showed better XP Gscores, ADME properties, and binding-free energies compared to 6MB, DrugBank compounds, and published inhibitors. The proposed leads were also validated by receiver operative characteristic (ROC) curve metrics in the presence of thousand decoys and the best docked existing compounds against DHPS. Long-range molecular dynamics (MD) simulations for 100 ns were executed after post-docking evaluations. Trajectory analysis showed the lead-DHPS docking complex's inter-molecular interactions were stable throughout the entire runtime of MD simulations than 6MB-DHPS complex and Eliglustat-DHPS complex. The study outcomes showed good competitive binding propensity and active-tunneling of leads over the existing inhibitors, thereby these leads could be ideal inhibitors against DHPS to target H. pylori .

The cascade of complications by Helicobacter pylori including extra-gastric and peptic ulcers to gastric cancer imposes a salient cause of cancer death globally. Adverse drug reactions and burgeoned genetically diverse resistant strains create a big barrier in the treatment, thereby demanding novel proof-of-concept ligands and breakthrough medicines. Hence, as a follow-up of the previous proteomics study against 53 H. pylori strains, KdsB was identified as a vital conserved-target enzyme. Herein, the rational therapeutic-design strategies exploiting for such a hidden cryptic inhibitor were utilized in lead-optimization campaigns through shape screening, the powerful scaffold-hopping, rigid-receptor, quantum-polarized ligand and induced-fit docking techniques coupled with estimating molecular-mechanics energies (ΔG bind ) through generalized-Born and surface-area-continuum solvation. Variable-dielectric-Surface-Generalized Born, a novel energy model and physics-based corrections for bond-interactions and ADME/Tox predictions led to yield improved eight therapeutic chemical entities with positive synthesizability scores (0-1). Long-range molecular dynamics (300 ns) simulations revealed stability of leads. Significant computational findings with better competitive binding-strengths than experimental ligands could pave the best choice for selecting better leads as it warrants and filter false-positives based on the consensus of scaffolds interactions and suggesting that designed novel class of KdsB-antagonist molecules may dysfunction the target and stimulate new insights for developing effectual medical interventions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A myriad of drug-resistant strains of Helicobacter pylori and adverse drug-reactions create a big-barrier in the treatment, thereby demanding novel proof-of-concept inhibitors and breakthrough medicines. Hence, an affinity-centric protocol was devised to implement scaffold-design for 3-dehydroquinate dehydratase-II (AroQ) as a follow-up of our study against beaucoup strains. Herein, the study focuses on preferred the attractive-target methodically due to its salient features include conserving, essential and specific for H. pylori, not present in humans and gut-flora. Structural refinement, energy minimization and optimization of the developed best-model were employed with confirming active site residues around substrate. Published AroQ-inhibitors and substrate were utilized to probe an in-house library of molecules. The prepared dataset was allowed to lead-optimization campaign includes rigid-receptor docking through high-throughput virtual, standard-precision, extra-precision screening filters, quantum-polarized-ligand (quantum mechanical and molecular mechanical (QM/MM)) and induced-fit docking experiments. Convergence threshold (0.05) and Truncated Newton Conjugate Gradient (TNCG) were set in ConfGen's algorithm to produce high-quality bioactive conformations by thoroughly narrowing the conformational space accessible to the leads. ADME/Tox predictions and long-range molecular dynamics simulations were executed after post-docking evaluations. The approach provided seven ranked compounds with better scoring functions, bioactive-conformers and pharmacokinetics profiles than published ligands and substrate. Simulations revealed more consistency of lead1-AroQ complex throughout chemical time than controls in the formulated physiological milieu. The study outcomes showing the good competitive binding propensity for active-tunnel over the substrate and previous ligands, thereby these leads could be ideal for proposing as selective cutting-edge inhibitors to target AroQ specific for H. pylori strains., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The developing potent vaccine is a pre-emptive strategy to tackle drug abuses and maladies of multidrug-resistant Helicobacter pylori strains. Ongoing vaccine studies are being conducted, however, development is in its infancy as ineffective vaccine targets might be. So, the linear perspective may indicate the need for potent subunit vaccine variants. Here, surface-exposed membrane proteins out of 826 common proteins of 53  H. pylori strains were chosen for analysis, as a follow-up to previous studies; these proteins are responsible for antigenicity to elicit the immune response. Antigenic determinant regions on prognostic targets were evaluated in the successive peptide screening using experimental T-cell epitope positive control and optimized with eminent immunoinformatics algorithms. In the milieu of docking, an ensemble of 2200 multiple conformers of complexes of modeled peptide and human leukocyte antigen- antigenD Related Beta-chain (HLA-DRB) was generated. Prioritized physics-based Molecular Mechanics-Generalized Born Surface Area approach coupled with bond length monitoring paved the improvement of prediction accuracy with binding potency estimations. Δ G bind free energy, interaction patterns, enrichment factor contributions and root-mean-square deviation predictions evidenced the existence of better binding affinities of four novel peptides hits with predominant allotype HLA-DR alleles than co-crystal controls. Moreover, conformational plasticity and stability assessments of the better ranked complex epitope-2 (86-FRRNPNINV-94) - HLA-DRB5*0101 formulated in dynamic simulations of 10,416 trajectories depicted stable interaction profile that correlated with docking endpoints. Thus, the proposed novel vaccine cocktails of the study would be ideal candidates and provide new insights for T-cell driven subunit vaccine design against H. pylori strains Communicated by Ramaswamy H. Sarma.

Introduction: Treatment failures of standard regimens and new strains egression are due to the augmented drug resistance conundrum. These confounding factors now became the drug designers spotlight to implement therapeutics against Helicobacter pylori strains and to safeguard infected victims with devoid of adverse drug reactions. Thereby, to navigate the chemical space for medicine, paramount vital drug target opting considerations should be imperative. The study is therefore aimed to develop potent therapeutic variants against an insightful extrapolative, common target LpxC as a follow-up to previous studies., Methods: We explored the relationships between existing inhibitors and novel leads at the scaffold level in an appropriate conformational plasticity for lead-optimization campaign. Hierarchical-clustering and shape-based screening against an in-house library of > 21 million compounds resulted in panel of 11,000 compounds. Rigid-receptor docking through virtual screening cascade, quantum-polarized-ligand, induced-fit dockings, post-docking processes and system stability assessments were performed., Results: After docking experiments, an enrichment performance unveiled seven ranked actives better binding efficiencies with Zinc-binding potency than substrate and in-actives (decoy-set) with ROC (1.0) and area under accumulation curve (0.90) metrics. Physics-based membrane permeability accompanied ADME/T predictions and long-range dynamic simulations of 250 ns chemical time have depicted good passive diffusion with no toxicity of leads and sustained consistency of lead1-LpxC in the physiological milieu respectively., Conclusions: In the study, as these static outcomes obtained from this approach competed with the substrate and existing ligands in binding affinity estimations as well as positively correlated from different aspects of predictions, which could facilitate promiscuous new chemical entities against H. pylori ., (© Biomedical Engineering Society 2019.)

Gastric cancer risk and adverse ramifications by augmented multi-drug resistance (MDR) of Helicobacter pylori are alarming serious health concern. Combating through available drugs is a difficult task due to lack of appropriate common targets against genetically diverse strains. To improve efficacy, the effective targets should be identified and critically assessed. In the present study, we aim to predict the potential novel targets against H. pylori strains by employing computer aided approach. The genomic dataset of 53 H. pylori strains was comparatively processed and eventually predicted 826 'conserved gene products'. Further, we performed subtractive genomic approach in search of promising crucial targets through the combination of in silico analyses. Codon adaptation index (CAI) value calculation and literature surveys were also done in order to find highly expressed gene products with novelty. Consequently, four enzymes and three membrane proteins were prioritized as new therapeutic and vaccine targets respectively which found to have more interactors in network with high-confidence score, druggability, antigenicity and molecular weight <110 kDa. Therefore, our results underpin the importance of new targets may counteract with false-positive/negatives and facilitate appropriate potential targets for a new insight of reliable therapeutic development., (Copyright © 2018. Published by Elsevier Ltd.)

c-Jun-NH2 terminal kinases (JNKs) come under a class of serine/threonine protein kinases and are encoded by three genes, namely JNK1, JNK2 and JNK3. Human JNK1 is a cytosolic kinase belonging to mitogen-activated protein kinase (MAPK) family, which plays a major role in intracrinal signal transduction cascade mechanism. Overexpressed human JNK1, a key kinase interacts with other kinases involved in the etiology of many cancers, such as skin cancer, liver cancer, breast cancer, brain tumors, leukemia, multiple myeloma and lymphoma. Thus, to unveil a novel human JNK1 antagonist, receptor-based pharmacophore modeling was performed with the available eighteen cocrystal structures of JNK1 in the protein data bank. Eighteen e-pharmacophores were generated from the 18 cocrystal structures. Four common e-pharmacophores were developed from the 18 e-pharmacophores, which were used as three-dimensional (3D) query for shape-based similarity screening against more than one million small molecules to generate a JNK1 ligand library. Rigid receptor docking (RRD) performed using GLIDE v6.3 for the 1683 compounds from in-house library and 18 cocrystal ligands with human JNK1 from lower stringency to higher stringency revealed 17 leads. Further to derive the best leads, dock complexes obtained from RRD were studied further with quantum-polarized ligand docking (QPLD), induced fit docking (IFD) and molecular mechanics/generalized Born surface area (MM-GBSA). Four leads have showed lesser binding free energy and better binding affinity towards JNK1 compared to 18 cocrystal ligands. Additionally, JNK1-lead1 complex interaction stability was reasserted using 50 ns MD simulations run and also compared with the best resolute cocrystal structure using Desmond v3.8. Thus, the results obtained from RRD, QPLD, IFD and MD simulations indicated that lead1 might be used as a potent antagonist toward human JNK1 in cancer therapeutics.