Molecular Mechanism of Cynodon dactylon Phytosterols Targeting MAPK3 and PARP1 to Combat Epithelial Ovarian Cancer: A Multifaceted Computational Approach.

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (-10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (-10.4 kcal/mol and -10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of -10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (-36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.

Multireceptor Analysis for Evaluating the Antidiabetic Efficacy of Karanjin: A Computational Approach.

BACKGROUND: Diabetes mellitus, notably type 2, is a rising global health challenge, prompting the need for effective management strategies. Common medications such as metformin, insulin, repaglinide and sitagliptin can induce side effects like gastrointestinal disturbances, hypoglycemia, weight gain and specific organ risks. Plant-derived therapies like Karanjin from Pongamia pinnata present promising alternatives due to their historical use, holistic health benefits and potentially fewer adverse effects. This study employs in silico analysis to explore Karanjin's interactions with diabetes-associated receptors, aiming to unveil its therapeutic potential while addressing the limitations and side effects associated with conventional medications. METHODOLOGY: The research encompassed the selection of proteins from the Protein Data Bank (PDB), followed by structural refinement processes and optimization. Ligands such as Karanjin and standard drugs were retrieved from PubChem, followed by a comprehensive analysis of their ADMET profiling and pharmacokinetic properties. Protein-ligand interactions were evaluated through molecular docking using AutoDockTools 1.5.7, followed by the analysis of structural stability using coarse-grained simulations with CABS Flex 2.0. Molecular dynamics simulations were performed using Desmond 7.2 and the OPLS4 force field to explore how Karanjin interacts with proteins over 100 nanoseconds, focusing on the dynamics and structural stability. RESULTS: Karanjin, a phytochemical from Pongamia pinnata, shows superior drug candidate potential compared to common medications, offering advantages in efficacy and reduced side effects. It adheres to drug-likeness criteria and exhibits optimal ADMET properties, including moderate solubility, high gastrointestinal absorption and blood-brain barrier penetration. Molecular docking revealed Karanjin's highest binding energy against receptor 3L2M (Pig pancreatic alpha-amylase) at -9.1 kcal/mol, indicating strong efficacy potential. Molecular dynamics simulations confirmed stable ligand-protein complexes with minor fluctuations in RMSD and RMSF, suggesting robust interactions with receptors 3L2M. CONCLUSION: Karanjin demonstrates potential in pharmaceutical expansion for treating metabolic disorders such as diabetes, as supported by computational analysis. Prospects for Karanjin in pharmaceutical development include structural modifications for enhanced efficacy and safety. Nanoencapsulation may improve bioavailability and targeted delivery to pancreatic cells, while combination therapies could optimize treatment outcomes in diabetes management. Clinical trials and experimental studies are crucial to validate its potential as a novel therapeutic agent.

Synthesis, biological evaluation, molecular docking, and MD simulation of novel 2,4-disubstituted quinazoline derivatives as selective butyrylcholinesterase inhibitors and antioxidant agents.

Alzheimer's disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer's disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer's treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

Erratum: Exploring HMMR as a therapeutic frontier in breast cancer treatment, its interaction with various cell cycle genes, and targeting its overexpression through specific inhibitors.

[This corrects the article DOI: 10.3389/fphar.2024.1361424.].

Natural products can be potential inhibitors of metalloproteinase II from Bacteroides fragilis to intervene colorectal cancer.

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.

Anti-quorum sensing activity of α-amidoamides against Agrobacterium tumefaciensNT1: Insights from molecular docking and dynamic investigations to synergistic approach of metronidazole release from gel formulations.

A unique approach is imperative for the development of drugs aimed at inhibiting various stages of infection, rather than solely focusing on bacterial viability. Among the array of unconventional targets explored for formulating novel antimicrobial medications, blocking the quorum-sensing (QS) system emerges as a highly effective and promising strategy against a variety of pathogenic microbes. In this investigation, we have successfully assessed nine α-aminoamides for their anti-QS activity using Agrobacterium tumefaciensNT1 as a biosensor strain. Among these compounds, three (2, 3and, 4) have been identified as potential anti-QS candidates. Molecular docking studies have further reinforced these findings, indicating that these compounds exhibit favorable pharmacokinetic profiles. Additionally, we have assessed the ligand's stability within the protein's binding pocket using molecular dynamics (MD) simulations and MMGBSA analysis. Further, combination of antiquorum sensing properties with antibiotics viaself-assembly represents a promising approach to enhance antibacterial efficacy, overcome resistance, and mitigate the virulence of bacterial pathogens. The release study also reflects a slow and gradual release of the metronidazole at both pH 6.5 and pH 7.4, avoiding the peaks and troughs associated with more immediate release formulations.

Exploring fingerprints for antidiabetic therapeutics related to peroxisome proliferator-activated receptor gamma (PPARγ) modulators: A chemometric modeling approach.

This study demonstrated the correlation of molecular structures of Peroxisome proliferator-activated receptor gamma (PPARγ) modulators and their biological activities. Bayesian classification, and recursive partitioning (RP) studies have been applied to a dataset of 323 PPARγ modulators with diverse scaffolds. The results provide a deep insight into the important sub-structural features modulating PPARγ. The molecular docking analysis again confirmed the significance of the identified sub-structural features in the modulation of PPARγ activity. Molecular dynamics simulations further underscored the stability of the complexes formed by investigated modulators with PPARγ. Overall, the integration of many computational approaches unveiled key structural motifs essential for PPARγ modulatory activity that will shed light on the development of effective modulators in the future.

Repurposing of FDA-approved drugs against oligomerization domain of dengue virus NS1 protein: a computational approach.

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.

Flavor Perception and Formation Mechanism of Empty Cup Aroma in Soy Sauce Aroma Type Baijiu.

The research focused on the distinctive empty cup aroma, with the aim of identifying the key aroma compounds and the formation mechanism of empty cup aroma in soy sauce aroma type baijiu (SSB). The lasting times of SSB is significantly longer than that of other types of baijiu, with an average duration of 28 days. Key compounds such as 2,3-dimethyl-5-ethylpyrazine, phenylethyl alcohol, p-cresol, sotolon, benzeneacetic acid were identified in empty cup aroma due to their highest flavor dilution factor. Molecular dynamics (MD) simulation was performed to study the mechanism of empty cup aroma on the liquid-gas interface and solid-gas interface. The results revealed the existence of hydrogen bonding and van der Waals forces between sotolon and lactic acid, a representative nonvolatile compound, which are speculated to be an important reason for the empty cup aroma.

Betulin: a novel triterpenoid anti-cancerous agent targeting cervical cancer through epigenetic proteins.

Worldwide, cervical cancer (CCa) is a major killer of women. As the conventional drugs used to treat cervical cancer are expensive and expose severe side effects, there is a growing demand to search for novel modifications. Therefore, in the current investigation employing a bioinformatic approach, we explored triterpenoids for their anti-cancer efficacy by targeting cervical cancer epigenetic proteins, namely DNMT3A, HDAC4, and KMT2C. The study utilized molecular docking, ADMET assay, Molecular Dynamic simulation, and DFT calculation to unveil Betulin (BE) as the potential lead compound. Comparative analysis with that standard drug indicated that BE has a better glide score with the target protein KM2TC (- 9.893 kcal/mol), HDAC4 (- 9.720 kcal/mol), and DNMT3A (- 7.811 kcal/mol), which depicts that BE could be a potent inhibitor of these three epigenetic proteins and exhibits favorable pharmacokinetic, pharmacodynamics and toxicity properties. Molecular Dynamics simulation revealed noteworthy structural stability and compactness. DFT analysis revealed higher molecular activity of BE and showed the most increased kinetic stability (δE = 0.254647 eV). Further, we employed In vitro analysis through MTT assay and found that BE has IC50 of 15 µg/ml. In conclusion, BE can potentially treat CCa upon further investigations using in vivo models for better understanding.

Preliminary Investigation of Astragalus arpilobus subsp. hauarensis: LC-MS/MS Chemical Profiling, In Vitro Evaluation of Antioxidant, Anti-Inflammatory Properties, Cytotoxicity, and In Silico Analysis against COX-2.

The search results offer comprehensive insights into the phenolic compounds, antioxidant, anti-inflammatory, cytotoxic effects, LC-MS/MS analysis, molecular docking, and MD simulation of the identified phenolic compounds in the Astragalus arpilobus subsp. hauarensis extract (AAH). The analysis revealed substantial levels of total phenolic content (TPC), with a measured value of 191 ± 0.03 mg GAE/g DM. This high TPC was primarily attributed to two key phenolic compounds: total flavonoid content (TFC) and total tannin content (TTC), quantified at 80.82 ± 0.02 mg QE/g DM and 51.91 ± 0.01 mg CE/g DM, respectively. LC-MS/MS analysis identified 28 phenolic compounds, with gallic acid, protocatechuic acid, catechin, and others. In the DPPH scavenging assay, the IC50 value for the extract was determined to be 19.44 ± 0.04 µg/mL, comparable to standard antioxidants like BHA, BHT, ascorbic acid, and α-tocopherol. Regarding anti-inflammatory activity, the extract demonstrated a notably lower IC50 value compared to both diclofenac and ketoprofen, with values of 35.73 µg/mL, 63.78 µg/mL, and 164.79 µg/mL, respectively. Cytotoxicity analysis revealed significant cytotoxicity of the A. arpilobus extract, with an LC50 value of 28.84 µg/mL, which exceeded that of potassium dichromate (15.73 µg/mL), indicating its potential as a safer alternative for various applications. Molecular docking studies have highlighted chrysin as a promising COX-2 inhibitor, with favorable binding energies and interactions. Molecular dynamic simulations further support chrysin's potential, showing stable interactions with COX-2, comparable to the reference ligand S58. Overall, the study underscores the pharmacological potential of A. arpilobus extract, particularly chrysin, as a source of bioactive compounds with antioxidant and anti-inflammatory properties. Further research is warranted to elucidate the therapeutic mechanisms and clinical implications of these natural compounds.

Comparative analysis of Doxycycline and Ayurvedic herbs to target metastatic breast cancer: An in-silico approach.

Background: Metastasis of breast cancer cells to distant sites including lungs, liver, lymph node, brain and many more have substantially affected the overall survival outcome and distant metastasis free survival rate amongst the diseased individuals. Several pre-clinical and clinical studies were carried out to determine the potency of vigorous inhibitors but they extensively deteriorated the patient's quality of life. Hence, there exists an urgent need to explore potent natural remedy to fight against metastatic breast cancer. Methods: Ayurvedic medicinal plants documented in literature for their ability to fight against breast cancer was screened and their respective active moieties were evaluated to exert inhibitory effect against MMP9. Drug like efficacy of phytochemicals were determined using Molecular docking, MD Simulation, ADMET and MM-PBSA and were further compared with synthetic analogs i.e. Doxycycline. Results: Out of 1000 phytochemicals, 12 exerted highest binding affinity (BA) even more than -9.0 kcal/mol that was significantly higher in comparison to Doxycycline which exhibited BA of -7.3 kcal/mol. In comparison to 37 × 30 × 37 Å, 53 × 45 × 66 Å offered best binding site and the highest BA was exhibited by Viscosalactone at LYS104, ASP185, MET338, LEU39, ASN38. During MD Simulation, Viscosalactone-MMP9 complex remained stable for 20 ns and the kinetic, electrostatic and potential energies were observed to be better than Doxycycline. Furthermore, Viscosalactone obtained from Withania somnifera justified the Lipinski's Rule of 5. Conclusion: Viscosalactone obtained from W. somnifera may act as promising drug candidate to fight against metastatic breast cancer.

In silico design of peptide inhibitors for Dengue virus to treat Dengue virus-associated infections.

Dengue virus is a single positive-strand RNA virus that is composed of three structural proteins including capsid, envelope, and precursor membrane while seven non-structural proteins (NS1, NS2A, NS2B, NS3A, NS3B, NS4, and NS5). Dengue is a viral infection caused by the dengue virus (DENV). DENV infections are asymptomatic or produce only mild illness. However, DENV can occasionally cause more severe cases and even death. There is no specific treatment for dengue virus infections. Therapeutic peptides have several important advantages over proteins or antibodies: they are small in size, easy to synthesize, and have the ability to penetrate the cell membranes. They also have high activity, specificity, affinity, and less toxicity. Based on the known peptide inhibitor, the current study designs peptide inhibitors for dengue virus envelope protein using an alanine and residue scanning technique. By replacing I21 with Q21, L14 with H14, and V28 with K28, the binding affinity of the peptide inhibitors was increased. The newly designed peptide inhibitors with single residue mutation improved the binding affinity of the peptide inhibitors. The inhibitory capability of the new promising peptide inhibitors was further confirmed by the utilization of MD simulation and free binding energy calculations. The molecular dynamics simulation demonstrated that the newly engineered peptide inhibitors exhibited greater stability compared to the wild-type peptide inhibitors. According to the binding free energies MM(GB)SA of these developed peptides, the first peptide inhibitor was the most effective against the dengue virus envelope protein. All peptide derivatives had higher binding affinities for the envelope protein and have the potential to treat dengue virus-associated infections. In this study, new peptide inhibitors were developed for the dengue virus envelope protein based on the already reported peptide inhibitor.

Mechanism of 7H-Dibenzo[c,g]carbazole metabolism in cytochrome P450 1A1: Insights from computational studies.

7H-Dibenzo[c,g]carbazole (DBC) is a prevalent environmental contaminant that induces tumorigenesis in several experimental animals. Recently, it has been utilized to develop high-performance solar cells and organic phosphorescent materials. It is imperative to strengthen investigations of DBC metabolism to understand its potential risks to human health. In this study, human CYP1A1 was employed as the metabolic enzyme to investigate the metabolic mechanism of DBC by molecular docking, molecular dynamics (MD) simulation, and quantum mechanical (QM) calculation. The results indicate that DBC binds to CYP1A1 in two modes (mode 1 and mode 2) mainly through nonpolar solvation energies (ΔGnonpolar). The formation of the two binding modes is attributed to the anchoring effect of the hydrogen bond formed by DBC with Asp320 (mode 1) or Ser116 (mode 2). Mode 1 is a "reactive" conformation, while mode 2 is not considered a "reactive" conformation. C5 is identified as the dominant site, and the pyrrole nitrogen cannot participate in the metabolism. DBC is metabolized mainly by a distinct electrophilic addition-rearrangement mechanism, with an energy barrier of 21.74 kcal/mol. The results provide meaningful insights into the biometabolic process of DBC and contribute to understanding its environmental effects and health risks.

Identification of structural fingerprints among natural inhibitors of HDAC1 to accelerate nature-inspired drug discovery in cancer epigenetics.

Histone deacetylase 1 (HDAC1), a class I HDAC enzyme, is crucial for histone modification. Currently, it is emerged as one of the important biological targets for designing small molecule drugs through cancer epigenetics. Along with synthetic inhibitors different natural inhibitors are showing potential HDAC1 inhibitions. In order to gain insights into the relationship between the molecular structures of the natural inhibitors and HDAC1, different molecular modelling techniques (Bayesian classification, recursive partitioning, molecular docking and molecular dynamics simulations) have been applied on a dataset of 155 HDAC1 nature-inspired inhibitors with diverse scaffolds. The Bayesian study showed acceptable ROC values for both the training set and test sets. The Recursive partitioning study produced decision tree 1 with 6 leaves. Further, molecular docking study was processed for generating the protein ligand complex which identified some potential amino acid residues such as F205, H28, L271, P29, F150, Y204 for the binding interactions in case of natural inhibitors. Stability of these HDAC1-natutal inhibitors complexes has been also evaluated by molecular dynamics simulation study. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints among different natural compounds modulating HDAC1 inhibition.Communicated by Ramaswamy H. Sarma.

Unraveling the potential of uninvestigated thermoalkaliphilic lipases by molecular docking and molecular dynamic simulation: an in silico characterization study.

Thermoalkaliphilic lipase enzymes are mostly favored for use in the detergent industry. While there has been considerable research on Geobacillus lipases, a significant portion of these enzymes remains unexplored or undocumented in the scientific literature. This work performed in silico phylogeny, sequence alignment, structural and enzyme-substrate interaction analyses of the five thermoalkaliphilic lipases belonging to different Geobacillus species (Geobacillus stearothermophilus lipase = GsLip, Geobacillus sp. B4113_201601 lipase = Gb4Lip, Geobacillus kaustophilus HTA426 lipase = GkLip, Geobacillus sp. SP22 lipase = GspLip, Geobacillus sp. NTU 03 lipase = GntLip). For this purpose, unreviewed enzyme sequences of five Geobacillus thermoalkaliphilic lipases were analyzed at sequence and phylogeny levels. 3D homology enzyme models were built, validated, and investigated by different bioinformatics tools. The ligand interactions screening using seven para-nitrophenyl (pNP) esters and enzyme-ligand interactions were analyzed on Gb4Lip:pNP-C12 and BTL2:pNP-C12 by MD simulation. Biophysicochemical characteristic analysis showed that Gb4Lip had a theoretical T m value of above 65 ºC, and a higher aliphatic index indicating greater thermal stability. Sequence alignment showed a hydrophilic threonine in the α6 helix of Gb4Lip, indicating high enzymatic activity. A normalized temperature factor B (B'-factor) analysis showed that the lid domains of five lipases significantly possessed lower B'-factor values, compared to G. thermocatenulatus lipase 2 (BTL2), indicating that they had higher rigidity. Molecular docking results indicated that the five lipases had the highest binding affinity toward pNP-C12. The RMSF investigation revealed that the thermostability of Gb4Lip is influenced by specific molecular elements: D202-S203 within the αB region of the lid domain, and E274-Q275 within the b3 strand, as well as W278 in the b3-b4 loop, and H282 in the b4 strand of the Ca2+-binding region. MD simulation analysis showed that catalytic residue S114 and at least one oxyanion hole residue (F17 and/or Q114) in Gb4Lip frequently formed hydrogen bonds with the pNP-C12 ligand at 343 K and 348 K throughout the simulation process, indicating that Gb4Lip might catalyze relatively long-chain ligand pNP-C12 with high performance. In conclusion, Gb4Lip might be a more suitable candidate as the detergent additive. In addition, this investigation can offer valuable perspectives on Family I.5 lipases such as Gb4Lip for future exploration in the field of protein engineering. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04023-5.

Analyzing energetics and dynamics of hepatitis C virus polymerase interactions with marine bacterial compounds: a computational study.

Hepatitis C Virus (HCV) is a significant health concern affecting a large portion of the global population and is a major cause of acute liver diseases, including cirrhosis. The variability in the HCV genome mainly results from the rapid replication facilitated by the NS5B polymerase, making it a prime target for anti-HCV drug development. This study explores potential compounds from marine bacteria that could inhibit the HCV NS5B polymerase by virtual screening, analyzing the energetics, and dynamic behavior of target-compound complexes. Virtual screening with the Lipinski filter was employed to select compounds from the marine bacteria database that demonstrated strong binding affinity to NS5B. The top four (CMNPD27216, CMNPD21066, CMNPD21065, and CMNPD27283) compounds, ranked by their re-docking scores, underwent additional evaluation. Molecular dynamics simulations for 200 ns were conducted to assess the dynamic stability of these complexes in a solvent environment. Furthermore, methods such as MM-GBSA, PCA, and free energy landscape analysis were used to analyze the system's energetics and identify stable conformations by locating transition states. The findings suggest that these compounds exhibit promising binding capabilities to HCV polymerase and could be considered for future experimental validation.

Insights into the dynamic interactions of RNase a and osmolytes through computational approaches.

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.

Quantum synergy in peptide folding: A comparative study of CVaR-variational quantum eigensolver and molecular dynamics simulation.

One of the technological fields that is developing the fastest is quantum computing in biology. One of the main problems is protein folding, which calls for precise, effective algorithms with fast computing times. Mapping the least energy conformation state of proteins with disordered areas requires enormous computing resources. The current study uses quantum algorithms, such as the Variational Quantum Eigensolver (VQE), to estimate the lowest energy value of 50 peptides, each consisting of seven amino acids. To determine the ground state energy value, Variational Quantum Optimisation (VQE) is first utilised to generate the energy values along with Conditional Value at Risk (CVaR) as an aggregation function is applied over 100 iterations of 500,000 shots each. This is contrasted with 50 millisecond molecular dynamics-based simulations to determine the energy levels and folding pattern. In comparison to MD-based simulations, the results point to CvaR-VQE producing more effective folding outcomes with respect to sampling and global optimization. Protein folding can be solved to get deep insights into biological processes and drug formulation with improving quantum technology and algorithms.

Catechin-Induced changes in PODXL, DNMTs, and miRNA expression in Nalm6 cells: an integrated in silico and in vitro approach.

BACKGROUND: This study explored the impact of predicted miRNAs on DNA methyltransferases (DNMTs) and the PODXL gene in Nalm6 cells, revealing the significance of these miRNAs in acute lymphocytic leukemia (ALL). METHODS: A comprehensive approach was adopted, integrating bioinformatic analyses encompassing protein structure prediction, molecular docking, dynamics, and ADMET profiling, in conjunction with evaluations of gene and miRNA expression patterns. This methodology was employed to elucidate the therapeutic potential of catechin compounds in modulating the activity of DNA methyltransferases (DNMTs) and the PODXL gene. RESULTS: The findings from our investigation indicate that catechins possess the capability to inhibit DNMT enzymes. This inhibitory effect is associated with the upregulation of microRNAs miR-200c and miR-548 and a concurrent downregulation of PODXL gene expression. These molecular interactions culminate in an augmented apoptotic response within ALL (Nalm6) cells. CONCLUSION: The study posits that catechins may represent a viable therapeutic avenue for inducing apoptosis in ALL cells. This is achieved through the modulation of epigenetic mechanisms and alterations in gene expression profiles, highlighting the potential of catechins as agents for cancer therapy.