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Diabetes mellitus is a globally prevalent disease of significant concern. Alpha-glucosidase has emerged as a prominent target for the treatment of type 2 diabetes. In this study, 39 α-glucosidase inhibitors (AGIs) of tetrahydrobenzo[b]thiophene-2-ylurea derivatives to establish a stable and valid Topomer CoMFA model, with a cross-validation coefficient (q²) of 0.766 and a non-cross-validation coefficient (r²) of 0.960. Subsequently, the ZINC15 database was used to screen the fragments, based on which 13 novel inhibitor molecules with theoretically potentially high activity were designed. Molecular docking and molecular dynamics simulations to understand the binding status of the inhibitor molecules to the target proteins showed that amino acids ASP215, GLN279 and ARG442 may form hydrogen bonds with the ligands and therefore enhance the inhibitory effect of the small molecules. Additionally, MM/PBSA calculations suggest that the newly designed molecules demonstrate more stable binding modes, and these newly designed molecules showed good ADMET properties with potential as AGIs. The findings would provide valuable guidance and a theoretical foundation for the design and development of novel AGIs.

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This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

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Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, hence there is an urgent need for new and effective therapeutic options. DNA topoisomerase 2A (TOP2A) plays a crucial role in the cell cycle and is involved in CRC progression, making it essential to identify structural and functional relevant alterations. Among the 24 mutations, our findings indicated that mutation D1021Y has the most deleterious effect on the TOP2A protein. Based on virtual screening of 31,561 compounds, we identified three lead candidates: 17683 (nigrospoxydon C), 28461 (carpatamide D), and 28853 (6'-O-acetyl-isohomaarbutin), which showed promising inhibitory effect against TOP2A and its mutant form. These compounds were assessed for their stability using density functional theory (DFT) analysis, where carpatamide D possessed the least energy gap of 4.398 eV showing its high reactivity among all. Further, molecular docking also shows the carpatamide D as the top candidate, which exhibited favourable docking energy against the TOP2A wild type (- 7.47 kcal/mol) and with D1021Y mutant (- 7.62 kcal/mol) as compared to reference compound PK1, which showed - 6.11 kcal/mol TOP2A wild type and - 6.24 kcal/mol against mutant type. The molecular dynamics simulation was performed to analyse the dynamics and stability of complex, which revealed TOP2A_28641 and D1021Y_28641 complexes to be stable with least root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF). Molecular mechanics/Poisson-Boltzmann surface area calculations indicated that TOP2A_28641 and D1021Y_28641 complexes exhibited the lowest binding energy of - 23.55 kcal/mol and - 25.03 kcal/mol, respectively. Our findings suggest carpatamide D as a promising lead compound for the TOP2A_D1021Y targeted cancer therapies, which needs further experimental validation.

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Multiple myeloma is recognized as the second most common hematological cancer. MafA transcriptional repressor is an established mediator of myelomagenesis. While there are multitude of drugs available for targeting various effectors in multiple myeloma, current literature lacks a candidate RNA based MafA modulator. Thus, using the structure of MafA homodimer-consensus target DNA, a computational effort was implemented to design a novel RNA based chemical modulator against MafA. First, available MafA-consensus DNA structure was employed to generate an RNA library. This library was further subjected to global docking to select the most plausible RNA candidates, preferring to bind DNA binding region of MafA. Following global docking, MD-ready complexes that were prepared via local docking program, were subjected to 500 ns of MD simulations. First, each of these MD simulations were analyzed for relative binding free energy through MM-PBSA method, which pointed towards a strong RNA based MafA binder, RNA1. Second, through a detailed MD analysis, RNA1 was shown to prefer binding to a single monomer of the dimeric DNA binding domain of MafA using higher number of hydrophobic interactions compared with positive control MafA-DNA complex. At the final phase, a principal component analyses was conducted, which led us to identify the actual interaction region of RNA1 and MafA monomer. Overall, to our knowledge, this is the first computational study that presents an RNA molecule capable of potentially targeting MafA protein. Furthermore, limitations of our study together with possible future implications of RNA1 in multiple myeloma were also discussed.

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Dysregulation in Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is closely linked to various cancer types. The N-terminal domain (NTD) of STAT proteins, upon dimerization, assumes a multifaceted role with remarkable adaptability in mediating interactions between proteins. Consequently, the strategic targeting of the N-terminal domain of STATs has emerged as a promising tactic for disrupting dimerization and impeding the translocation of STAT proteins. In this study, we have deployed an integrated in-silico methodology to rationally design Peptidomimetic foldamers as inhibitors of the N-terminal domains of STAT3 and STAT4, with the objective of disrupting protein dimerization. Consequently, we have judiciously designed a series of peptidomimetics that encompass ß3-amino acids, bearing side chains that mimic the residues within interface II of the dimeric structures of the NTDs. Employing molecular docking techniques; we have assessed the binding affinity of these designed peptidomimetics toward both the NTDs. Furthermore, we have conducted an evaluation of the stability and conformational alterations within the docked complexes over an extensive Molecular Dynamics, subsequently computing the binding free energy utilizing MM/PBSA calculations. Our findings unequivocally demonstrate that the peptidomimetic foldamers we have devised (Peptide-A, Peptide-B, and Peptide-C) exhibit a propensity to bind to and impede the dimerization process of the NTDs of both STAT3 and STAT4. These outcomes serve to underscore the potential of these meticulously designed peptidomimetics as potential candidates meriting further exploration in the realm of cancer prevention and management.

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Seizures, depression, and anxiety are neurological disorders that affected innumerable people worldwide. Recent research has revealed that targeting 5-hydroxytryptamine 2 (5-HT2) receptors can help suppress these conditions. An in-depth literature study has identified that phytocompounds from the Boerhavia genus could reduce seizures. Therefore, homology models of 5-HT2 receptors were generated and validated using techniques such as the alignment of amino acid sequences and the Ramachandran plot. Later, a comparison of modeled structures was made with a non-redundant set of PDB structures. The pharmacokinetics, drug-likeness, blood-brain barrier (BBB) permeability, and Lipinski's rule of five shed light on 22 phytocompounds, which are the potential candidates for molecular docking among 127 Boerhavia's bioactive. Notably, molecular docking analysis revealed 4',7-dihydroxy-3'-methylflavone as the most potent lead compound, which has a strong binding affinity to all modeled receptors. Additionally, with a remarkably high docking score of -9.1 kcal/mol, 4',7-dihydroxy-3'-methylflavone showed promising interactions, particularly with 5-HT2A receptor, as seen from the RMSD, SASA, Rg, and number of hydrogen bonds during 100 ns molecular dynamic (MD) simulation. Principal component analysis (PCA) and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) further confirmed that 4',7-dihydroxy-3'-methylflavone is the best novel phytocompound in Boerhavia genus for 5-HT2 receptor as agonist/antagonist activity against seizures.

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Phenolic environmental endocrine-disrupting chemicals (PEDCs) are persistent EDCs that are widely found in food packaging materials and environmental media and seriously threaten human health and ecological security. Human estrogen-related receptor γ (hERRγ) has been proposed as a mediator for the low-dose effects of many environmental PEDCs; however, the atomic-level descriptions of dynamical structural features and interactions of hERRγ and PEDCs are still unclarified. Herein, how three PEDCs, 4-(1-methylpropyl)phenol (4-sec-butylphenol), 5,6,7,8-tetrahydro-2-naphthol (tetrahydro-2-napthol), and 2,2-bis(4-hydroxy-3,5-dimethoxyphenyl)propane (BP(2,2)(Me)), interact with hERRγ to produce its estrogenic disruption effects was studied. Molecular docking and multiple molecular dynamics (MD) simulations were first conducted to distinguish the detailed interaction pattern of hERRγ with PEDCs. These binding structures revealed that residues around Leu271, Leu309, Leu345, and Phe435 are important when binding with PEDCs. Furthermore, the binding energies of PEDCs with hERRγ were also characterized using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) and solvated interaction energy (SIE) methods, and the results showed that the interactions of CH-π, π-π, and hydrogen bonds are the major contributors for hERRγ binding to these three PEDCs. What is striking is that the methoxide groups of BP(2,2)(Me), as hydrophobic groups, can help to reduce the binding energy of PEDCs binding with hERRγ. These results provide important guidance for further understanding the influence of PEDCs on human health problems.

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SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit-protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of -161.49 kJ/mol, -151.28 kJ/mol, and -107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of -71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer.

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Bacteroides fragilis, a gram negative and obligate anaerobe bacterium, is a member of normal gut microbiota and facilitates many essential roles being performed in human body in normal circumstances specifically in Gastrointestinal or GI tract. Sometimes, due to genetics, epigenetics, and environmental factors, Bacteroides fragilis and their protein(s) start interacting with intestinal epithelium thus damaging the lining leading to colorectal cancers (CRC). To identify these protein(s), we incorporated a novel subtractive proteomics approach in the study. Metalloproteinase II (MPII), a Bacteroides fragilis toxin (bft), was investigated for its virulence and unique pathways to demonstrate its specificity and uniqueness in pathogenicity followed by molecular docking against a set of small drug-like natural molecules to discover potential inhibitors against the toxin. All these identified inhibitor-like molecules were analyzed for their ADMET calculations and detailed physiochemical properties to predict their druggability, GI absorption, blood brain barrier and skin permeation, and others. Resultantly, a total of ten compounds with the least binding energies were obtained and were subjected to protein-compound interaction analysis. Interaction analysis revealed the most common ligand-interacting residues in MPII are His 345, Glu 346, His 339, Gly 310, Tyr 341, Pro 340, Asp 187, Phe 309, Lys 307, Ile 185, Thr 308, and Pro 184. Therefore, top three compounds complexed with MPII having best binding energies were selected in order to analyze their trajectories. RMSD, RMSF, Rg and MMPBSA analysis revealed that all compounds showed good binding and keeping the complex stable and compact throughout the simulation time in addition to all properties and qualities of being a potential inhibitor against MPII.

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Bis-intercalators play a significant role in altering the DNA structure, affecting its stability, and potentially influencing various cellular processes. These compounds have gained considerable attention in medicinal chemistry and biochemistry due to their potential applications in cancer therapy, where they may interfere with DNA replication and transcription, leading to anticancer effects. Traditionally, these molecules often possess a high positive charge to enhance their affinity for the negatively charged DNA. However, due to a high positive charge, their cellular uptake is compromised, along with their enhanced potential off-target effects. In this study, we utilized bis-intercalator TOTO and replaced the charged linker segment (propane-1,3-diammonium) with a neutral peroxodisulphuric acid linker. Using molecular modeling and computer simulations (500 ns, 3 replicas), we investigated the potential of the designed molecule as a bis-intercalator and compared the properties with the control bis-intercalator bound to DNA. We observed that the designed bis-intercalator exhibited improved DNA binding (as assessed through MM-PBSA and Delphi methods) and membrane translocation permeability. With an overall reduced charge, significantly less off-target binding of the designed molecule is also anticipated. Consequently, bis-intercalators based on peroxodisulphuric linkers can potentially target DNA effectively, and their role in the future design of bis-intercalators is foreseen.

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Dengue fever is a serious health hazard on a global scale and its primary causative agent is the dengue virus (DENV). The non-structural protein 1 (NS1) of DENV plays a pivotal role in pathogenesis. It is associated with several autoimmune events, endothelial cell apoptosis, and vascular leakage, which increase mainly during the critical phase of infection. In this study, important residues of the oligomerization domain of NS1 protein were identified by literature searches. Virtual screening has been conducted using the entire dataset of the DrugBank database and the potential small-molecule inhibitors against the NS1 protein have been chosen on the basis of binding energy values. This is succeeded by molecular dynamics (MD) simulations of the shortlisted compounds, ultimately giving rise to five compounds. These five compounds were further subjected to RAMD simulations by applying a random direction force of specific magnitude on the ligand center of mass in order to push the ligand out of the protein-binding pocket, for the quantitative estimation of their binding energy values to determine the interaction strength between protein and ligand which prevents ligand unbinding from its binding site, ultimately leading to the selection of three major compounds, DB00826 (Natamycin), DB11274 (Dihydro-alphaergocryptine), and DB11275 (Epicriptine), with the DB11274 having a role against idiopathic Parkinson's disease, and thus may have possible important roles in the prevention of dengue-associated Parkinsonism. These compounds may act as prospective drugs against dengue, by preventing the oligomerization of the NS1 protein, thereby preventing disease progression and pathogenesis.

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CONTEXT: Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by ß-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence. METHODS: For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, ß-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. RESULTS: Molecular docking studies showed that the Lumacaftor- ß-catenin complex had the lowest docking score of - 8.7 kcal/mol towards ß-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-ß-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study.

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Bacillus anthracis, the causative agent of anthrax, poses a substantial threat to public health and national security, and is recognized as a potential bioweapon due to its capacity to form resilient spores with enduring viability. Inhalation or ingestion of even minute quantities of aerosolized spores can lead to widespread illness and fatalities, underscoring the formidable lethality of the bacterium. With an untreated mortality rate of 100%, Bacillus anthracis is a disconcerting candidate for bioterrorism. In response to this critical scenario, we employed state-of-the-art computational tools to conceive and characterize flexible RNA aptamer therapeutics tailored for anthrax. The foundational structure of the flexible RNA aptamers was designed by removing the C2'-C3' in each nucleotide unit. Leveraging the crystal structure of Bacillus anthracis ribosomal protein S8 complexed with an RNA aptamer, we explored the structural, dynamic, and energetic aspects of the modified RNA aptamer - S8 protein complexes through extensive all-atom explicit-solvent molecular dynamics simulations (400 ns, 3 replicas each), followed by drawing comparisons to the control system. Our findings demonstrate the enhanced binding competencies of the flexible RNA aptamers to the S8 protein via better shape complementarity and improved H-bond network compared to the control RNA aptamer. This research offers valuable insights into the development of RNA aptamer therapeutics targeting Bacillus anthracis, paving the way for innovative strategies to mitigate the impact of this formidable pathogen.

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Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE2). The frequent mutations in the receptor-binding domain (RBD) of the spike protein induced the emergence of variants with increased contagion and can hinder vaccine efficiency. Hence, it is crucial to better understand the binding mechanisms of variant RBDs to human ACE2 and develop efficient methods to characterize this interaction. In this work, we present an approach that uses machine learning to analyze the molecular dynamics simulations of RBD variant trajectories bound to ACE2. Along with the binding free energy calculation, this method was used to characterize the major differences in ACE2-binding capacity of three SARS-CoV-2 RBD variants-namely the original Wuhan strain, Omicron BA.1, and the more recent Omicron BA.5 sublineages. Our analyses assessed the differences in binding free energy and shed light on how it affects the infectious rates of different variants. Furthermore, this approach successfully characterized key binding interactions and could be deployed as an efficient tool to predict different binding inhibitors to pave the way for new preventive and therapeutic strategies.

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Osmolytes are small organic molecules that are known to stabilize proteins and other biological macromolecules under various stressful conditions. They belong to various categories such as amino acids, methylamines, and polyols. These substances are commonly known as 'compatible solutes' because they do not disrupt cellular processes and help regulate the osmotic balance within cells. In the case of ribonuclease A (RNase A), which is prone to aggregation, the presence of osmolytes can help to maintain its structural stability and prevent unwanted interactions leading to protein aggregation. In this study, we investigated the interaction between RNase A and several osmolytes using molecular docking and molecular dynamics (MD) simulations. We performed molecular docking to predict the binding mode and binding affinity of each osmolyte with RNase A. MD simulations were then carried out to investigate the dynamics and stability of the RNase A-osmolyte complexes. Our results show that two osmolytes, glucosylglycerol and sucrose have favorable binding affinities with RNase A. The possible role of these osmolytes in stabilizing the RNase A and prevention of aggregation is also explored. By providing computational insights into the interaction between RNase A and osmolytes, the study offers valuable information that could aid in comprehending the mechanisms by which osmolytes protect proteins and help in designing therapeutics for protein-related disorders based on osmolytes. These findings may have significant implications for the development of novel strategies aimed at preventing protein misfolding and aggregation in diverse disease conditions.Communicated by Ramaswamy H. Sarma.

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In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([125I]anastrozole) and radioiodinated epirubicin ([125I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [125I]anastrozole and [125I]epirubicin with MTHFD2. Molecular docking illustrates that [125I]epirubicin has a superior binding free energy (∆Gbind) of -41.25 kJ/mol compared to -39.07 kJ/mol for [125I]anastrozole and -38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme-ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [125I]anastrozole and [125I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[125I]anastrozole and 16.84 Å for MTHFD2-[125I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [125I]anastrozole and [125I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of -48.49 ± 0.11 kJ/mol for [125I]anastrozole and -43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [125I]anastrozole and [125I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [125I]anastrozole and [125I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results.

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DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

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Alzheimer's disease (AD) presents a significant challenge in neurodegenerative disease management, with limited therapeutic options available for its prevention and treatment. At the heart of AD pathogenesis is the amyloid-ß (Aß) protein precursor (APP), with the interaction between APP and the adaptor protein Mint2 being crucial. Despite previous explorations into the APP-Mint2 interaction, the dynamic regulatory mechanisms by which Mint2 modulates APP binding remain poorly understood. This study undertakes molecular dynamics simulations across four distinct systems-free Mint2, Mint2 bound to APP, a mutant form of Mint2, and the mutant form bound to APP-over an extensive 400 ns timeframe. Our findings reveal that the mutant Mint2 experiences significant secondary structural transformations, notably the formation of an α-helix in residues S55-K65 upon APP binding, within the 400 ns simulation period. Additionally, we observed a reduction in the active pocket size of the mutant Mint2 compared to its wild-type counterpart, enhancing its APP binding affinity. These insights hold promise for guiding the development of novel inhibitors targeting the Mints family, potentially paving the way for new therapeutic strategies in AD prevention and treatment.

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Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.

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CONTEXT: Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50 ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. METHOD: Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses.

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