Molecular Dynamics Simulation Approach Research Articles

Exploring quinoline-type inhibitors of ergosterol biosynthesis: Binding mechanism investigation via molecular docking, pharmacophore mapping, and dynamics simulation approaches.

Drug-resistant fungal infections pose a formidable challenge in healthcare, attributed to ergosterol production as a key mechanism of resistance. It is therefore imperative to target this pathway for effective therapeutic interventions. In this study, we have analyzed the binding mode of twelve quinoline derivatives known to be effective against various Candida species, Microsporum gypseum, and Cryptococcus neoformans. Employing molecular docking techniques, pharmacological modeling, and molecular dynamics, we have delved into interactions with Erg1, Erg11, and Erg24 proteins, crucial in ergosterol biosynthesis. Our analysis unveiled critical interactions that facilitate the docking and stabilization of C-2-substituted quinoline derivatives on these proteins, highlighting their potential as regulators of ergosterol synthesis. Furthermore, complexes formed with Erg1 … 8 (MIC=125μg/mL) and Erg24 … 4 (MIC=62μg/mL) showed higher affinity and stability during the docking process, pointing to their promising role as regulatory agents of these proteins. This in silico approach provides insights into potential pathways to combat drug-resistant fungal infections.

Integrated Clinomics and Molecular Dynamics Simulation Approaches Reveal the SAA1.1 Allele as a Biomarker in Alkaptonuria Disease Severity

Alkaptonuria (AKU) is a rare metabolic disorder characterized by the accumulation of homogentisic acid (HGA), leading to progressive ochronosis and joint degeneration. While much is known about HGA’s role in tissue damage, the molecular mechanisms underlying acute inflammation in AKU remain poorly understood. Serum amyloid A (SAA) proteins are key mediators of the inflammatory response, yet their potential as biomarkers for inflammation in AKU has not been explored. This study investigated the role of the SAA1.1 allele as a biomarker for the severity of acute inflammation in AKU. Data from the ApreciseKUre Precision Medicine Ecosystem were analyzed to assess the relationship between SAA1 allelic variants and inflammatory markers. Molecular dynamics simulations compared the structural dynamics of SAA1.1 and SAA1.2 isoforms, with standard modeling and analysis pipelines employed. Using a clinomics approach, we showed that AKU patients expressing the SAA1.1 allele have significantly higher acute inflammation-related markers. Extensive molecular dynamics simulations revealed that the SAA1.1 isoform lent high structural instability of the C-terminal domain, accelerating the formation of amyloid fibrils and exacerbating the inflammatory condition. These findings would identify the SAA1.1 allele as a novel genetic biomarker for the progression of secondary amyloidosis in AKU and its severity. Furthermore, new molecular insights into the inflammatory mechanisms of AKU were provided, suggesting potential therapeutic approaches aimed at stabilizing SAA1.1 protein and preventing amyloid fibril formation, with significant implications in AKU and precision medicine strategies for SAA-related diseases.

Structure-Activity Relationship of Ciprofloxacin towards S-Spike Protein of SARS-CoV-2: Synthesis and In-Silico Evaluation.

The recent outbreak of the coronavirus (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has posed serious threats to global health systems. Although several directions have been put by the WHO for effective treatment, use of antibiotics, particularly ciprofloxacin, in suspected and acquired Covid-19 patients has raised an even more serious concern of antibiotic resistance. Ciprofloxacin has been reported to inhibit entry of SARS-CoV-2 into the host cells via interacting with the spike (S) protein. However, a proper structure-activity relationship study of ciprofloxacin with the S-protein is lacking, which inhibits researchers from developing a more potent fluoroquinolone analogue, specific for inhibition of SARS-CoV-2 viral entry. Herein, in order to have a structure-activity relationship study, we have accomplished a short and convergent synthesis of different derivatives of ciprofloxacin and a detailed in-silico study using molecular docking to explore the interactions of the derivatives with S-protein. The ADMET studies also indicated the drug likeliness and nontoxicity of the derivatives. Furthermore, the molecular dynamics simulation approach was used to study the dynamical behavior after the best docked derivative binds to the protein, and the MM-PBSA approach was adopted to calculate the binding energies. This has led to a derivative that has higher interactions with the S-protein compared to ciprofloxacin, without hampering the dynamics of the interactions. The strong affinity of compound 5 with the SARS-CoV-2 spike RBD protein was further evaluated experimentally using biolayer interferometry (BLI). Furthermore, molecular docking and molecular dynamics simulation were extended to evaluate its binding with the mutated variants Delta and Omicron. We anticipate that the current study could lead to an alternative therapeutic viral inhibitor with a better efficacy than ciprofloxacin.

Computational Evaluation of Punica granatum Leaf Phytochemicals against Multi-drug Resistant E. coli: Molecular Docking, ADMET, MD Simulation, and DFT Studies.

Multidrug-resistant (MDR) E. coli presents a significant challenge in clinical settings, necessitating the exploration of novel therapeutic agents. Phytochemicals from Punica granatum (pomegranate) leaves have shown potential antibacterial properties. This study aims to identify and evaluate the efficacy of these phytochemicals against MDR E. coli. This study aims to identify and evaluate the efficacy of most potential phytochemical of Punica granatum leaf against MDR E. coli. through molecular docking, adme, toxicity, molecular dynamic simulation, MMPBSA and DFT approaches. We performed molecular docking of 11 phytochemicals from the IMPPAT database with four MDR E. coli targets: 1AJ6, 1FJ8, 4BJP, and 6BU3. Granatin B demonstrated the best binding affinity and was further analyzed. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analyses were conducted to assess its pharmacokinetic properties and safety profile. Molecular Dynamics (MD) simulations were performed to evaluate the stability of Granatin B with the targets. Finally, density functional theory (DFT) analysis was carried out to understand the electronic properties and reactivity of Granatin B. Granatin B exhibited the highest binding affinity among the 11 phytochemicals, indicating strong potential as an inhibitor of MDR E. coli. ADME analysis revealed favorable pharmacokinetic properties and toxicity analysis confirmed that Granatin B is non-toxic. MD simulations showed stable interactions between Granatin B and all four targets. DFT analysis provided insights into the electronic properties and reactive sites of Granatin B, supporting its potential mechanism of action. Granatin B from Punica granatum leaves is a promising candidate for treating MDR E. coli infections. The integration of molecular docking, ADME, toxicity, MD simulations, and DFT analysis underscores its therapeutic potential and paves the way for further experimental validation and development as a novel antibacterial agent.

Identification of Lauric Acid as a Potent Sodium Channel NaV1.5 Blocker from Compound Chinese Medicine Wenxin Keli.

The major cardiac voltage-gated sodium channel NaV1.5 (INa) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of INa in WXKL and exploring their mode of action in electrophysiological conduction. A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the NaV1.5 gene SCN5A. Candidate fractions with INa-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. NaV1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches. A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the NaV1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for INa-inhibition with an IC50 at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of INa to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel INa blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the NaV1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na+. Mechanistically, lauric acid acts on the fast inactivation of NaV1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL. Lauric acid is a potent blocker for sodium channel NaV1.5 and alleviates arrhythmia via inhibiting INa.

SBL-JP-0004: A promising dual inhibitor of JAK2 and PI3KCD against gastric cancer.

Gastric cancer (GC) remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional therapies. The phosphoinositide 3-kinase and PI3K and Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathways play pivotal roles in GC progression, making them attractive targets for therapeutic interventions. This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of JAK2 and PI3KCD kinases. KATOIII and SNU-5 GC cells were used for in vitro evaluation. SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases, as evidenced by molecular docking scores and molecular dynamics simulations. Binding interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target proteins. SBL-JP-0004 displayed an half-maximal inhibitory concentration (IC50) value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD enzymes. SBL-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with half-maximal growth inhibitory concentration (GI50) values of 250.8 and 516.3 nM, respectively. A significant elevation in the early phase apoptosis (28.53% in KATOIII cells and 26.85% in SNU-5 cells) and late phase apoptosis (17.37% in KATOIII cells and 10.05% in SNU-5 cells) were observed with SBL-JP-0004 treatment compared to 2.1% and 2.83% in their respective controls. The results highlight SBL-JP-0004 as a promising dual inhibitor targeting JAK2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.

Investigation of bioremediation for glyphosate and its metabolite in soil using arbuscular mycorrhizal GmHsp60 protein: a molecular docking and molecular dynamics simulations approach

Investigation of bioremediation for glyphosate and its metabolite in soil using arbuscular mycorrhizal GmHsp60 protein: a molecular docking and molecular dynamics simulations approach

Comparative analysis of backbone atom cross-correlation matrices and folding dynamics of amyloid fibril and its complexes with novel biosurfactants isolated from Bacillus strain: a binding free energy calculation (mM-PBSA) and MD simulation approach

In the relentless pursuit of unraveling the intricate pathophysiology of Alzheimer’s disease (AD), amyloid β (Aβ) proteins emerge as focal points due to their pivotal role in disease progression. The pathological hallmark of AD involves the aberrant aggregation of Aβ peptides into amyloid fibrils, precipitating a cascade of neurodegenerative events culminating in cognitive decline and neuronal loss. This study adopts a computational framework to investigate the potential therapeutic efficacy of novel biosurfactants (BS) in mitigating Aβ fibril formation. Initial analyses encompassing sequence alignment, structural elucidation, and functional characterization reveal distinctive attributes of the Aβ peptide and the identified BS candidates. Quantum chemical calculations, using the ORCA Program (v4.0) employed Density Functional Theory (DFT), specifically the Becke 3-parameter Lee-Yang-Parr (B3LYP) method, to investigate the electronic structure and energetics of novel isolates. Molecular docking through AutoDock Vina (version 1.1.2) employing advanced algorithms elucidates the binding affinities and interaction energies between Aβ fibrils and BS molecules. The observed binding energy of −7.0 kcal/mol for BG2A and −6.6 kcal/mol for BG2B, underscoring the robustness and stability of the formed complexes. The binding mechanism of docked complexes was predicted through molecular dynamics (MD) simulations using GROMACS 2021.3 and Charmm36 force field, capture complex dynamics over 100 nanoseconds. Analysis via RMSD, RMSF, Rg, PCA, and SASA offers insights into Aβ-BS complex stability and dynamics. These promising results highlight the potential of BG2A and BG2B as therapeutic candidates against AD. However, rigorous preclinical and clinical validation is crucial to ascertain their safety, efficacy, and translational relevance.

Predictive Insights Into Bioactive Compounds from Streptomyces as Inhibitors of SARS-CoV-2 Mutant Strains by Receptor Binding Domain: Molecular Docking and Dynamics Simulation Approaches

Background: The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) receptor in humans. To date, numerous SARS-CoV-2 variants, particularly those involving mutations in the RBD, have been identified. These variants exhibit differences in transmission, pathogenicity, diagnostics, and vaccine efficacy. Objectives: Although therapeutic agents are currently available to inhibit SARS-CoV-2, most provide supportive and symptomatic relief. Moreover, different variants may exhibit resistance to these treatments. This study aimed to identify a potential compound with favorable antiviral effects against SARS-CoV-2 variants. Methods: The study explored drug discovery through structure-based virtual screening of natural products (NPs) from the StreptomeDB database, targeting the ACE2-binding pocket of the SARS-CoV-2 RBD protein. The analysis included the wild-type protein (PDB ID: 6VW1) as well as the Alpha, Beta, Delta, Lambda, Omicron/BA.1, and Omicron/BA.2 variants. Results: In silico screening identified ‘Stambomycin B’ as a potential compound with the highest binding affinity. Molecular dynamics simulations of the complexes, conducted over 100 ns, confirmed the prediction that ‘Stambomycin B’ could inhibit different SARS-CoV-2 variants effectively. Conclusions: This study concludes that ‘Stambomycin B’, a macrolide compound produced by Streptomycesambofaciens, may be a candidate NP for effectively combating all mutants that occur in the binding of SARS-CoV-2 RBD to ACE2, even those that may arise in the future.

Exploring phytochemical inhibitors of protein kinase C alpha for therapeutic targeting of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy. Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial. In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database. Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of selected compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability of the interactions. Finally, we propose two phytochemicals, Kammogenin and Imperialine, with appreciable drug-likeliness and binding potential with PKCα. Taken together, the findings suggest Kammogenin and Imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.

Fungal secondary metabolites as a potential inhibitor of T315I- BCR::ABL1 mutant in chronic myeloid leukemia by molecular docking, molecular dynamics simulation and binding free energy exploration approaches

BackgroundChronic Myeloid Leukemia (CML) is particularly challenging to treat due to the T315I BCR::ABL1 mutation. Although fungal metabolites are known for their pharmaceutical potential, none are approved for CML. Our study screened approximately 2000 fungal secondary metabolites to discover inhibitors targeting the T315I- BCR::ABL1 mutant protein. MethodsWe conducted comprehensive analyses to elucidate the interactions between the T315I-BCR::ABL1 mutant protein and selected fungal metabolites. These analyses included molecular docking, ADMET assessment, molecular dynamics simulations, principal components analysis, exploration of free energy landscapes, and per-residue decomposition. ResultsWe identified a range of binding affinities for fungal secondary metabolites, from −11.2 kcal/mol to −2.90 kcal/mol, with the co-crystal ponatinib showing a binding affinity of −9.9 kcal/mol. Notably, twenty seven fungal metabolites had affinities ≤ -10.0 kcal/mol, surpassing ponatinib. Eight compounds, including Phellifuropyranone A and Meshimakobnol B, showed favorable drug-likeness. Molecular dynamics parameters, including RMSD, RMSF, Rg, and SASA, confirmed that Phellifuropyranone A and Meshimakobnol B bind stably to the T315I-BCR::ABL1 mutant protein. Additionally, PCA, DCCM, and free energy landscapes analyses validated the consistency of the molecular dynamics parameters. MM/PBSA analysis indicated that Phellifuropyranone A (–22.88 ± 4.28 kcal/mol) and Meshimakobnol B (−25.86 ± 3.51 kcal/mol) bind similarly to ponatinib (−25.54 ± 6.31 kcal/mol). Per-residue decomposition explored residues MET290, VAL299, ILE315, and PHE359 as crucial for binding to the T315I-BCR::ABL1 mutant protein. ConclusionsPhellifuropyranone A and Meshimakobnol B show significant potency as inhibitors of the T315I-BCR::ABL1 mutant protein, comparable to ponatinib. These compounds may serve as effective alternatives or synergistic agents with ponatinib, potentially overcoming drug resistance and improving treatment outcomes in Chronic Myeloid Leukemia.

From nature’s pharmacy: harnessing bioactive phytoconstituents as fibroblast growth factor receptor 3 inhibitors for anti-cancer therapeutics

Fibroblast growth factor receptor 3 (FGFR3) is a key protein involved in regulating cell growth and development. Aberrant activation of FGFR3 has been linked to several diseases, including cancer and skeletal disorders. Therefore, identifying potential inhibitors of FGFR3 is of great interest in developing targeted therapies. In this study, we employed a combined docking and molecular dynamics simulation (MDS) approach to investigate the inhibitory potential of plant-based compounds against FGFR3. Here, we utilized structure-based virtual screening to identify potential phytoconstituents from the IMPPAT library with the ability to inhibit FGFR3 activity. The initial screening process involved molecular docking to assess the binding potential of the compounds towards FGFR3. Afterward, we employed various filters to determine physicochemical properties, ADMET, and PASS evaluation to identify potential hits against FGFR3. This process discovered two phytoconstituents, Cycloartobiloxanthone and Desoxylimonin, as promising candidates against FGFR3. These compounds exhibited favorable binding affinity, efficiency, and specific interaction towards the FGFR3 binding pocket. They preferred binding to the active site of FGFR3 and possessed desirable drug-like properties. To gain a deeper understanding of their interaction mechanism, conformational dynamics, and stability, we conducted all-atom MDS lasting 200 nanoseconds (ns) on the FGFR3-Cycloartobiloxanthone and FGFR3-Desoxylimonin complexes. The MDS consistently demonstrated the formation of stable protein-ligand complexes between FGFR3 and Cycloartobiloxanthone/Desoxylimonin throughout the trajectory. Based on these results, it can be inferred that Cycloartobiloxanthone and Desoxylimonin can potentially serve as valuable scaffolds in developing drugs targeting FGFR3 for cancer therapeutic after required validation.

Exploring temperature effects on compatibility in PS‐b‐PI‐b‐PS block copolymer‐based blends through experimental and molecular dynamics simulation approaches

AbstractThe poly(styrene‐block‐isoprene‐block‐styrene) (PS‐b‐PI‐b‐PS) block copolymer is known for its self‐assembly characteristics and dual structure that combines rubber and thermoplastic materials. Conventionally, blends of block copolymers are fabricated using the melt blending method, a process that requires high temperatures. This study introduces an energy‐efficient solution blending method to enhance the compatibility between PS‐b‐PI‐b‐PS and natural rubber (NR) latex. NR latex was blended with PS‐b‐PI‐b‐PS in toluene at temperatures of 80, 100, 120, and 150°C and cast to form films. The solution‐blended film prepared at a moderate temperature of 120°C exhibited a maximum tensile strength of 9.48 MPa and was thermally degraded at higher temperature (382°C) than those produced by melt blending. The solution blending method also reduced the surface roughness and the particle size to between 7 and 500 nm and improved the interfacial adhesion in SB‐120°C blend compared to MB‐180°C blend. Molecular dynamics simulations indicated that the improved mechanical performance of the blend was primarily due to enhanced intramolecular bonding, with a maximized bond energy of 20,133 kcal/mol. This work demonstrates an energy‐efficient method with lower processing temperature for preparing polymer blends with improved compatibility suitable for various nanotechnology and engineering applications.Highlights Solution blending method improves the compatibility. Tensile strength and interfacial adhesion of the polymer blend improved. Solution blending reduces the particle size and surface roughness. Simulation shows an increase in intramolecular bond energy.

Molecular dynamics insight of interaction between Artemisinin and its derivatives and the cancer cell membrane

In the present study, a molecular dynamics simulation approach has been utilized to investigate the effectiveness of four molecules, including Artemisinin, a natural product, and its derivatives Dihydroartemisinin, Artesunate, and Artemisone, on a membrane of a cancerous cell. Performed simulations predicted that Dihydroartemisinin and Artemisone form stronger hydrogen bonds with the cancer membrane, exhibit higher mobility, and have a longer lifetime at the water-membrane interface. Artemisone molecules could penetrate the hydrophobic part of the lipid’s tail, leading to higher fluidity of the cancer membrane. These two compounds exerted the greatest effect on the properties and characteristics of the membrane model while showing stronger anti-cancer effects than the other two compounds. The simulation outcomes and predictions were found to agree with the results of experimental studies. It is noticeable that Dihydroartemisinin and Artemisone enter the cancer cell membrane from their functional group side, while Artemisinin and Artesunate enter from their peroxide ring side.

Pharmacotherapeutic potential of bilobetin to combat chromium induced hepatotoxicity via regulating TLR-4, Nrf-2/Keap-1, JAK1/STAT3 and NF-κB pathway: A pharmacokinetic and molecular dynamic approach

BackgroundChromium (Cr) is one of the top-notch noxious heavy metals that is documented to exert deleterious effects on various body organs including the liver. Bilobetin (BLB) is a natural flavonoid which exhibits a wide range of medicinal properties. AimThis trial was executed to investigate the pharmacotherapeutic potential of BLB to avert Cr instigated hepatotoxicity via modulating TLR4, JAK1/STAT3, Nrf-2/Keap-1 and NF-κB pathway. Research layoutOur trial was executed on thirty-six male albino rats that were segregated into four equal groups including the control, Cr (10 mg/kg), Cr (10 mg/kg) + BLB (12 mg/kg) and BLB (12 mg/kg) alone treated group. Various biochemical parameters were assessed by using qRT-PCR, molecular docking, molecular dynamic simulation and histological approaches. FindingsOur results revealed that Cr administration significantly impaired the health of hepatic tissues by reducing the gene expression of Nrf-2 and its downregulating genes while promoting the levels of oxidative stress markers (ROS and MDA). Moreover, Cr administration upregulated the hepatic enzymes including ALT, GGT, AST, and ALP while concurrently decreasing the levels of total protein and albumin. Cr exposure also elevated the gene expression of pro-inflammatory cytokines including toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) nuclear factor kappa B (NF-κB), Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor alpha (TNF-α), C-reactive proteins, interferon-gamma inducible protein-10 (IP-10), Interleukin beta-1(IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Hepatic apoptosis was observed to be elevated following the Cr intoxication. Nonetheless, BLB treatment remarkably alleviated the hepatic damages via regulating the biochemical as well as histological profile of liver. Our findings are further endorsed by molecular docking analysis that demonstrated that BLB exhibit strong binding affinity to Keap-1 and STAT3 thus supporting its efficient hepatoprotective potential. ConclusionBLB protected the hepatic tissues via regulating Cr induced impairments. These findings were confirmed by molecular docking and molecular dynamic simulation analysis.

Identification of Potential Inhibitors of Histone Deacetylase 6 Through Virtual Screening and Molecular Dynamics Simulation Approach: Implications in Neurodegenerative Diseases.

Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved. This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide. The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein-ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6-ligand complexes, confirming the stability of their interactions. The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.

Elucidating the interactions of advanced glycation end products with RAGE, employing molecular docking and MD simulation approaches: Implications of potent therapeutic for diabetes and its related complications

Diabetes mellitus is a global health challenge, ranking third among the mortality rates globally. Diabetic-mediated Advanced glycation end products (AGEs) associated with Receptor for Advanced Glycation End-products (RAGE) contribute to chronic diabetes and its complications, inflammatory, cancer, and neurodegenerative disorders. The information behind the binding mechanisms between AGEs-RAGE complexes remains elusive. In the current study, we used advanced computational approaches to reveal the intramolecular interactions of AGEs-RAGE which leads to multiple diseases. We have characterized AGEs-RAGE interactions by protein–ligand docking and molecular dynamic (MD) simulations were further conducted to evaluate the AGEs-RAGE complex stability. Subsequently, several residues emerged as pivotal in AGEs-RAGE complex formation. Further, MD simulation provides valuable insights into structural movements, stability, and conformational dynamics of protein–ligand complexes. Our findings underscore new insights into molecular mechanisms of AGEs-RAGE complex formation in diabetes and its related complications and the ease of the drug discovery process.

Probing marine macroalgal phlorotannins as an antibacterial candidate against Salmonella typhi: Molecular docking and dynamics simulation approach

The increasing prevalence of drug-resistant bacterial strains, including multidrug-resistant Salmonella typhi, has raised significant concerns about the effectiveness of traditional antimicrobial treatments. To address this issue, the study employed computational techniques to evaluate the potential of natural phlorotannins derived from marine algae as alternative antibacterial agents against S. typhi. A total of 104 phlorotannins were retrieved from PubChem and subjected to molecular docking with three specific target proteins of S. typhi. Among the compounds tested, Compound-10 a derivative of dieckol exhibited the highest affinity for the Omptin family outer membrane protease [pgtE] protein and for the cell invasion protein sipB protein. The docking results revealed strong interactions between the phlorotannins and the target proteins, indicating their potential as antimicrobial agents. Additionally, pharmacokinetic studies using the QikProp module demonstrated that the top-ranked compounds showed favourable drug-like properties with good druggable efficiency, moderate gut-blood barrier transport, and high human oral absorption. Most compounds passed the rule of three and five drug-likeness criteria, indicating their potential as drug candidates. Furthermore, MM-GBSA analysis provided relative binding affinity estimations, ranking the compounds based on their calculated binding energies. These results align reasonably well with experimental binding affinities, reinforcing the potential of the identified compounds as potent binders to their target proteins. This study highlights the promising antibacterial potential of marine phlorotannins against S. typhi. Further in vitro studies are warranted to validate these compounds' efficacy and anti-microbial activity, ultimately paving the way for developing new therapeutic strategies to combat drug-resistant Salmonella infections.

Adsorption of molecular hydrogen (H2) on a fullerene (C60) surface: insights from density functional theory and molecular dynamics simulation.

Understanding the adsorption behavior of molecular hydrogen (H2) on solid surfaces is essential for a variety of technological applications, including hydrogen storage and catalysis. We examined the adsorption of H2 (∼2800 configurations) molecules on the surface of fullerene (C60) using a combined approach of density functional theory (DFT) and molecular dynamics (MD) simulations with an improved Lennard-Jones (ILJ) potential force field. First, we determined the adsorption energies and geometries of H2 on the C60 surface using DFT calculations. Calculations of the electronic structure help elucidate underlying mechanisms administrating the adsorption process by revealing how H2 molecules interact with the C60 surface. In addition, molecular dynamics simulations were performed to examine the dynamic behavior of H2 molecules on the C60 surface. We accurately depicted the intermolecular interactions between H2 and C60, as well as the collective behavior of adsorbed H2 molecules, using an ILJ potential force field. Our findings indicate that H2 molecules exhibit robust physisorption on the C60 surface, forming stable adsorption structures with favorable adsorption energies. Calculated adsorption energies and binding sites are useful for designing efficient hydrogen storage materials and comprehending the nature of hydrogen's interactions with carbon-based nanostructures. This research provides a comprehensive understanding of H2 adsorption on the C60 surface by combining the theoretical framework of DFT calculations with the dynamical perspective of MD simulations. The outcomes of the present research provide new insights into the fields of hydrogen storage and carbon-based nanomaterials, facilitating the development of efficient hydrogen storage systems and advancing the use of molecular hydrogen in a variety of applications.

Cryptochrome magnetoreception: Time course of photoactivation from non-equilibrium coarse-grained molecular dynamics

Magnetoreception, the ability to sense magnetic fields, is widespread in animals but remains poorly understood. The leading model links this ability in migratory birds to the photo-activation of the protein cryptochrome. Magnetic information is thought to induce structural changes in cryptochrome via a transient radical pair intermediate. This signal transduction pathway has been the subject of previous all-atom molecular dynamics (MD) simulations, but insights were limited to short timescales and equilibrium structures. To address this, we developed a non-equilibrium coarse-grained MD simulation approach, exploring cryptochrome’s photo-reduction over 20 replicates of 20 µs each. Our results revealed significant structural changes across the protein, with an overall time constant of 3 µs. The C-terminal (CT) region responded on a timescale of 4.7 µs, followed by the EEE-motif, while the phosphate binding loop (PBL) showed slower dynamics (9 µs). Network analysis highlighted direct pathways connecting the tryptophan tetrad to the CT, and distant pathways involving the EEE and PBL regions. The CT-dynamics are significantly impacted by a rearrangement of tryptophan residues in the central electron transfer chain. Our findings underscore the importance of considering longer timescales when studying cryptochrome magnetoreception and highlight the potential of non-equilibrium coarse-grained MD simulations as a powerful tool to unravel protein photoactivation reactions.