Computational Prediction and In Vitro Validation of Potential Molecular Targets Associated with Adverse Reactions of Antimicrobial Drugs in Neonates.

In this study, we synthesized novel α,β-unsaturated 2-cyanoacetamide derivatives (1–5) using microwave-assisted Knoevenagel condensation. Characterization of these compounds was carried out using FTIR and 1H NMR spectroscopy. We then evaluated their in vitro antibacterial activity against both gram-positive and gram-negative pathogenic bacteria. Additionally, we employed in silico methods, including ADMET prediction and density functional theory (DFT) calculations of molecular orbital properties, to investigate these cyanoacetamide derivatives (1–5). Molecular docking was used to assess the binding interactions of these derivatives (1–5) with seven target proteins (5MM8, 4NZZ, 7FEQ, 5NIJ, ITM2, 6SE1, and 5GVZ) and compared them to the reference standard tyrphostin AG99. Notably, derivative 5 exhibited the most favorable binding affinity, with a binding energy of -7.7 kcal mol−1 when interacting with the staphylococcus aureus (PDB:5MM8), while also meeting all drug-likeness criteria. Additionally, molecular dynamics simulations were carried out to evaluate the stability of the interaction between the protein and ligand, utilizing parameters such as Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), Radius of Gyration (Rg), and Principal Component Analysis (PCA). A 50 nanosecond molecular dynamics (MD) simulation was performed to investigate stability further, incorporating RMSD and RMSF analyses on compound 5 within the active binding site of the modeled protein across different temperatures (300, 305, 310, and 320 K). Among these temperatures, compound 5 exhibited an RMSD value ranging from approximately 0.2 to 0.3 nm at 310 K (body temperature) with the 5MM8 target, which differed from the other temperature conditions. The in silico results suggest that compound 5 maintained significant conformational stability throughout the 50 ns simulation period. It is consistent with its low docking energy and in vitro findings concerning α,β-unsaturated cyanoacetamides.Key insights from this study include:•The creation of innovative α,β-unsaturated 2-cyanoacetamide derivatives (1–5) employing cost-effective, licensed, versatile, and efficient software for both in silico and in vitro assessment of antibacterial activity.•Utilization of FTIR and NMR techniques for characterizing compounds 1–5.

The sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban. Measurement of in-cell calcium dynamics supports this observation and demonstrates that DWORF increases SERCA-dependent calcium reuptake. These functional observations reveal opposing effects of DWORF activation and phospholamban inhibition of SERCA. To gain mechanistic insight into SERCA activation, fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium. Molecular modeling and molecular dynamics simulations provide a model for DWORF activation of SERCA, where DWORF modulates the membrane bilayer and stabilizes the conformations of SERCA that predominate during elevated cytosolic calcium.

This study aims to evaluate the predicted binding stability of the compound ecdysone in comparison with the native ligand, in order to determine its potential as an effective and stable antibacterial agent through molecular docking and molecular dynamics (MD) simulations. An exploratory computational approach was employed to assess the antibacterial activity, interaction patterns, and stability of compounds derived from Sida rhombifolia. A total of 15 bioactive compounds were docked against the molecular target PBP2a (PDB ID: 4JCN) using AutoDockTools and PyMol, followed by an analysis of amino acid residue similarity between each test ligand and the native ligand. The compound exhibiting the best interaction profile was further analyzed using MD simulation to evaluate its binding stability and pharmacokinetic properties. Validation parameters, including Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF), were calculated based on in silico predictions. MD simulations were conducted using YASARA Dynamics. The molecular docking results indicated that ecdysone demonstrated the highest binding affinity and interaction pattern comparable to that of the native ligand. The MD simulation further confirmed that ecdysone maintained stable binding throughout the simulation period, as reflected by RMSD and RMSF profiles of the MRSA target complex.

Introduction : The lack of knowledge regarding the incidence of adverse drug reactions in the hospital setting and their impact on morbidity and mortality is, nowadays, a major health problem in Angola. In the last years, notifications of adverse drug reactions have been practically null, namely at a hospital level. It is of great importance to characterize the incidence of adverse drug reactions occurring in a hospital setting, in order to implement measures towards improving the quality of healthcare services. Material and Methods: We conducted a descriptive, prospective observational study to characterize the incidence of adverse drug reactions (ADRs) in patients admitted to the Central Hospital “Josina Machel” in Luanda during the year 2014. An intensive monitoring through active search for adverse reactions possibly related with the drugs prescribed to patients was performed. Results : Of a total of 2041 hospitalized patients, 175 had adverse drug reactions. The incidence rate was 4.74% in the medicine service (n = 1077) and 12.86% in the therapy service (n = 964). A total of 209 adverse drug reactions were identified, averaging 1,2 adverse drug reactions per patient. The highest incidence rate of adverse drug reactions was recorded in patients aged between 18 and 35 years old, with 79 patients (45.14%). With regard to therapeutic class, it was found that antimicrobials were the drugs most commonly associated with adverse reactions, with 71 notifications (40.57%), followed by analgesics, antipyretics and anti-inflammatory steroids with 20,00%. Quinine and artesunate were the antimicrobials most frequently implicated in causing an adverse drug reaction, with 25 (14.29%) and 15 (8.57%) notifications respectively. In the group of anti-inflammatory drugs, diclofenac stood out with 13 notifications (7.43%). The most common clinical manifestations were skin rash, which corresponded to 23,44% of the total number of adverse drug reactions, followed by bleeding, which accounted for 8.6% of the number of adverse reactions registered (n = 18). Within the group of antimicrobials, antimalarials and cephalosporins were the drugs most commonly associated with skin lesions, with 27 notifications (55.10%). Most of adverse reactions were moderate in severity (66.86%) and were classified as probably drug-related (80.57%). Discussion and Conclusion : A high frequency of adverse drug reactions was found in hospitalized patients, particularly in the therapy service. It was evident the subnotification of adverse reactions by health professionals and the need for a system of notification of adverse reactions that combines passive and active surveillance for the prevention and detection of adverse drug reactions.

Background Poly (ADP-ribose) polymerase 1 (PARP1) is a critical enzyme involved in DNA repair mechanisms, making it a promising target for anticancer drug development. Triazole derivatives have shown potential as PARP1 inhibitors, but systematic evaluation of a large library remains limited. Objective To perform comprehensive in silico screening and molecular dynamics simulations of 180 triazole derivatives to identify potent PARP1 inhibitors and evaluate their binding stability and interaction profiles. Methods A library of 180 triazole derivatives was subjected to molecular docking against the active site of PARP1 using [Schrodinger suite 2024-4]. Top-ranking compounds based on binding affinity were selected for further molecular dynamics (MD) simulations using to assess the stability of the ligand–protein complexes over a 100 ns simulation period. Binding free energies were calculated using MM-GBSA approaches. Key protein–ligand interactions were analyzed to elucidate binding mechanisms. Results Docking results identified 10 triazole derivatives with superior binding affinities −9.4 to −5.5 kcal/mol compared to reference inhibitors. MD simulations confirmed stable binding conformations with root mean square deviation (RMSD) fluctuations within acceptable limits. Interaction analysis highlighted crucial hydrogen bonds and hydrophobic contacts with catalytic residues of PARP1. Conclusion The integrated in silico screening and molecular dynamics simulation approach successfully identified promising triazole derivatives as potential PARP1 inhibitors. These findings provide valuable insights for the rational design and optimization of novel anticancer agents targeting PARP1.

Tripartite motif (TRIM)7 is an E3 ubiquitin ligase that was first identified through its interaction with glycogenin-1 (GN1), the autoglucosyltransferase that initiates glycogen biosynthesis. A growing body of evidence indicates that TRIM7 plays an important role in cancer development, viral pathogenesis, and atherosclerosis and, thus, represents a potential therapeutic target. TRIM family proteins share a multidomain architecture with a conserved N-terminal TRIM and a variable C-terminal domain. Human TRIM7 contains the canonical TRIM motif and a B30.2 domain at the C terminus. To contribute to the understanding of the mechanism of action of TRIM7, we solved the X-ray crystal structure of its B30.2 domain (TRIM7B30.2) in two crystal forms at resolutions of 1.6 Å and 1.8 Å. TRIM7B30.2 exhibits the typical B30.2 domain fold, consisting of two antiparallel β-sheets of seven and six strands, arranged as a distorted β-sandwich. Furthermore, two long loops partially cover the concave face of the β-sandwich defined by the β-sheet of six strands, thus forming a positively charged cavity. We used sequence conservation and mutational analyses to provide evidence of a putative binding interface for GN1. These studies showed that Leu423, Ser499, and Cys501 of TRIM7B30.2 and the C-terminal 33 amino acids of GN1 are critical for this binding interaction. Molecular dynamics simulations also revealed that hydrogen bond and hydrophobic interactions play a major role in the stability of a modeled TRIM7B30.2-GN1 C-terminal peptide complex. These data provide useful information that could be used to target this interaction for the development of potential therapeutic agents.

Drug-induced pancreatitis is a gastrointestinal adverse effect concerning about 2% of drugs. The majority of cases are mild to moderate but severe episodes can also occur, leading to hospitalization or even death. Unfortunately, the mechanisms of this adverse reaction are still not clear, hindering its prevention, and the majority of data available of this potentially life-threatening adverse effect are limited to case reports leading to a probable underestimation of this event. In particular, in this editorial, special attention is given to thiopurine-induced pancreatitis (TIP), an idiosyncratic adverse reaction affecting around 5% of inflammatory bowel disease (IBD) patients taking thiopurines as immunosuppressants, with a higher incidence in the pediatric population. Validated biomarkers are not available to assist clinicians in the prevention of TIP, also because of the inaccessibility of the pancreatic tissue, which limits the possibility to perform dedicated cellular and molecular studies. In this regard, induced pluripotent stem cells (iPSCs) and the exocrine pancreatic differentiated counterpart could be a great tool to investigate the cellular and molecular mechanisms underlying the development of this undesirable event. This particular type of stem cells is obtained by reprogramming adult cells, including fibroblasts and leukocytes, with a set of transcription factors known as the Yamanaka’s factors. Maintaining unaltered the donors’ genetic heritage, iPSCs represent an innovative model to study the mechanisms of adverse drug reactions in individual patients’ tissues not easily obtainable from human probands. Indeed, iPSCs can differentiate under adequate stimuli into almost any somatic lineage, opening a new world of opportunities for researchers. Several works are already available in the literature studying liver, central nervous system and cardiac cells derived from iPSCs and adverse drug effects. However, to our knowledge no studies have been performed on exocrine pancreas differentiated from iPSCs and drug-induced pancreatitis, so far. Hence, in this editorial we focus specifically on the description of the study of the mechanisms of TIP by using IBD patient-specific iPSCs and exocrine pancreatic differentiated cells as innovative in vitro models.

Adverse drug reactions (ADR’s) are defined the effects created by drugs producing unintended or noxious response. Also, an ADR is a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease or for the modification of a physiological function. The evaluation of ADRs adapts various factors that can predispose patients to adverse reactions. The types of adverse reaction can be studies in two main headings, i.e., more common ADRs including type A and B reactions; and less common ADRs which include type C, D and E reactions. The present review article explains about the various types and mechanisms of adverse reactions.

An agenda for research on adverse drug reactions

Purpose: Little research has been conducted on adverse drug reactions in neonates, particularly in Korea, where no studies have been reported.Methods: We conducted a retrospectively study using medical records in a neonatal intensive care unit from August 1, 2013 to July 31, 2014.The adverse drug reactions were evaluated according to the Naranjo algorithm, World Health Organization-Uppsala Monitoring Centre, and the Korean adverse drug reaction algorithm.Results: Of the 410 infants hospitalized during the study period, 57 cases of adverse drug reactions were reported in 40 infants (9.8%).The average gestational age was 28.4±4.3weeks, the average birth weight was 1,184.1±622.0g, and the adverse drug reactions were reported at an average of 21.0±29.7 days after birth.Causative agents were identified as electrolytes (36.8%), respiratory medication (14.0%), total parenteral nutrition (12.3%), lipid emulsion (10.5%), antibiotics (7.0%), non-steroidal antiinflammatory drugs (NSAIDs, 7.0%), sedatives (7.0%), vaccine (3.5%), and an antiviral medication (1.8%).Of the 57 cases, 55 (96.5%) cases demonstrated meaningful adverse drug reactions, defined as those given a score of "possible or above" in all 3 adverse drug reaction algorithms.Conclusion: More emphasis is warranted in the field of neonatal adverse drug reactions.

Down Syndrome (DS), characterized by trisomy of chromosome 21, leads to the overexpression of several genes contributing to various pathologies, including cognitive deficits and early-onset Alzheimer's disease. This study aimed to identify the intersection genes of two polyphenolic compounds, apigenin and naringenin, and their potential therapeutic targets in DS using network pharmacology. Key proteins implicated in DS, comprising DYRK1A, APP, CBS, and ETS2, were selected for molecular docking and dynamics simulations to assess the binding affinities and stability of the protein-ligand interactions. Molecular docking revealed that naringenin exhibited the highest binding affinity to DYRK1A with a score of -9.3 kcal/mol, followed by CBS, APP, and ETS2. Moreover, molecular docking studies included positive control drugs, such as lamellarin D, valiltramiprosate, benserazide, and TK216, which exhibited binding affinities ranging from -5.5 to -8.9 kcal/mol. Apigenin showed strong binding to APP with a score of -8.8 kcal/mol, suggesting its potential in modulating amyloid-beta levels. These interactions were further validated through molecular dynamics simulations, demonstrating stable binding throughout the 100 ns simulation period. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses indicated minimal fluctuations, confirming the stability of the complexes. The findings suggest that apigenin and naringenin could serve as effective therapeutic agents for DS by targeting key proteins involved in its pathology. Future studies should focus on in vivo validation, clinical trials, and exploring combination therapies to fully harness the therapeutic potential of these compounds for managing DS. This study underscores the promising role of network pharmacology in identifying novel therapeutic targets and agents for complex disorders like DS.

BackgroundThe human microbiota plays a crucial role in maintaining host health and is involved in various illnesses, including cancer. The intestinal microbiota has been identified as a factor in the development of colorectal carcinoma and breast cancer (BC).ObjectivesThis study investigated the anticancer properties of bacteriocins produced by Lactobacillus acidophilus, specifically their interaction with receptor tyrosine kinase-like orphan receptor 1 (ROR-1), a protein involved in aggressive BC subtypes.MethodsEmploying sophisticated computational methodologies, encompassing molecular docking and molecular dynamics (MD) simulations, this research elucidated the dynamic interactions and binding strengths of four distinct bacteriocins — Acidocin A, Acidocin B, Acidocin 8912, and Acidocin J1132β — with the ROR-1 receptor. This observation was substantiated by consistent hydrogen bond formation and low root mean square deviation (RMSD) values throughout the simulation period. Furthermore, the biological activity of crude acidocins was evaluated on the ROR-1-Src signaling axis in Michigan Cancer Foundation-7 (MCF-7) and MDA-MB-231 cell lines utilizing Western blot analysis.ResultsThe findings of this research demonstrate that Acidocin A exhibits promise as a prospective therapeutic intervention directed at ROR-1 in BC. Furthermore, the synergistic application of molecular docking, MD simulations, and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) free energy calculations yielded a thorough elucidation of the underlying interaction mechanisms. The assessment of protein expression levels indicated a significant downregulation of the ROR-1-Src signaling pathway following treatment with Acidocins.ConclusionsThis research highlights the potential of bacteriocins in cancer treatment and adds to evidence linking the microbiota to cancer, establishing new pathways for anticancer therapies from microbial sources.

In this study, we have synthesized novel thiohydrazone 3(a-b) and hydrazone analogues 3(c) by one-pot methodology with good to excellent yields (85%-91%). In silico molecular dynamics (MD) simulations, docking, and absorption, distribution, metabolism, excretion and toxicity (ADMET) were evaluated as inhibitor activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PDB ID: 5N5O) main protease. The dynamics simulations studies and docking were conducted by GROMACS and AutoDock Vina. The ADMET studies of all the compounds were evaluated to understand drug-likeness and potential for therapeutic applications. All the synthesized compounds 3(a-c) exhibited strong docking scores between -5.0 and -5.4 kcal mol-1 to the targeted protein. MD simulations revealed that the 3b protein-ligand complex demonstrated conformational stability throughout most of the 70 ns simulation period with root mean square deviation (RMSD) fluctuations below 3 Å. ADMET predictions indicated that all compounds possessed high gastrointestinal absorption, suggesting good oral bioavailability. By slow evaporation technique, crystals of compound 3b were grown using ethanol and its single crystal X-ray diffraction analysis disclosed that it crystallized in the monoclinic (P21/c) crystal system. Crystal data outlined crystal packing, bond lengths, bond angles, intermolecular hydrogen bonding parameters, etc. This study offers further avenues in the discovery of novel and promising hydrazone analogues against SARS-CoV-2 main protease.

Objective: To analyze the clinical characteristics of adverse skin reactions (ADRs) caused by ginkgolide injection, and to provide reference for the post-marketing safety study of ginkgolide injection. Methods: By participating in the treatment of a patient with suspected adverse skin reactions caused by ginkgolide injection, The patient was given target ginkgolide injection 50mg intravenously once a day for two consecutive days due to cerebral infarction. Six days after drug withdrawal, the patient developed a rash on the buttocks, and then the rash quickly spread to the whole body, resulting in skin lesions with exudation tendency, itchy skin and extensive epidermal shedding. Combined with clinical medication and the clinical characteristics of this adverse reaction, the causes and mechanisms of adverse reactions caused by ginkgolide injection were analyzed from the ingredients of ginkgolide injection and the adverse reaction reports of ginkgolide extract. Consults: The adverse reaction was analyzed as severe skin allergy caused by ginkgolide injection. After oral administration of ebastine, injection of calcium gluconate and vitamin C, and topical dehumidification and itching-relieving ointment, the skin lesions basically healed after 2 weeks. Conclusions: Cases of skin allergic reactions caused by ginkgolide injection have been reported, but clinical trials on the safety of ginkgolide injection still lack the content of post-marketing safety studies. This adverse reaction is a detailed case analysis, in order to provide reference for the content of post-marketing safety of ginkgolide injection.

Diabetes mellitus is a chronic metabolic disorder that continues to rise globally, leading to severe health complications and economic burdens. Despite the availability of synthetic antidiabetic drugs, their side effects, limited efficacy, and long-term complications have driven interest in natural products as potential alternatives. Physalis angulata L. has been traditionally used for its anti-inflammatory, antioxidant, and hypoglycemic properties, but its molecular mechanisms in diabetes management remain unclear. This study employed network pharmacology (NP), molecular docking, and molecular dynamics (MD) simulations to systematically explore the bioactive compounds in Physalis angulata L. and their interactions with key diabetic targets. NP was utilized to predict compound-target interactions, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses to identify metabolic pathways involved in diabetes regulation. The predicted protein–protein interaction (PPI) networks were visualized using Cytoscape, revealing key targets linked to glucose metabolism and insulin sensitivity. To validate these predictions, molecular docking was performed to assess the binding affinity and stability of Physalis angulata L. metabolites with diabetic target proteins. The top-ranked compounds were further analyzed through MD simulations during a 50 ns simulation period, with root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analysis confirming their structural stability within the receptor binding sites. Binding free energy calculations using MM-PBSA provided additional validation of ligand-receptor interactions. The results identified quercetin and myricetin as the most promising multi-target antidiabetic compounds, exhibiting strong and stable interactions with multiple key diabetic receptors. This study highlights the potential of Physalis angulata L. as a natural source for diabetes treatment, demonstrating the effectiveness of computational approaches in identifying bioactive compounds with multi-target therapeutic potential.