Journal of Biomolecular Structure & Dynamics最新文献

The combination of clopidogrel and acetylsalicylic acid is the standard treatment for atherosclerotic cardiovascular disease. Nonetheless, there is a pressing need for more potent P2Y₁₂ receptor inhibitors with quicker onset, especially for early intervention in acute myocardial infarction. Integrating computational modeling, i.e. pharmacophore modeling, molecular docking, and dynamics, with empirical data guides the development of effective antiplatelet therapies. This multidisciplinary study employs computational modeling and in-vitro experimental analysis, demonstrating significant inhibition of P2Y₁₂ activity by two NCI compounds namely: NSC380324 and NSC618163. Both NSC380324 and NSC618163 exhibited a platelet reactivity index (%PRI) of 30.0% and 34.0%, respectively compared to cangrelor that demonstrated superior activity, with a %PRI of 11.0% in platelet vasodilator-stimulated phosphoprotein (VASP) assay. Molecular docking simulations show strong binding affinities of both compounds, along with strong binding interactions at the P2Y₁₂ binding site. Importantly, molecular dynamics simulations highlight the influence of receptor dynamics on practical efficacy, suggesting that NSC380324, a promising P2Y₁₂ antagonists indicated by its excellent stability profiles at the binding pocket of P2Y₁₂, its hydrogen-bond interactions occupancies and the average MM-PBSA total binding energy of -38.17 kcal/mol, require further structural optimization and in-vivo studies to realize their full potential for clinical application.

RbgA (ribosome biogenesis GTPase A) is involved in the maturation of later stages of the 50S ribosomal subunit by associating with the 45S ribosomal subunit. However, this binding relies on the specific nucleotide-bound state of RbgA-GTP-bound state is more favorable compared GDP-bound state, attributed to the conformational variations between those states. Therefore, to explore the conformational changes of RbgA, all-atom MD simulations of BsRbgA were carried out under various nucleotide bound states (GDP, GTP, GTP-Mg²⁺ and GMPPNP-Mg²⁺). The analysis of overall conformational changes using RMSD and Rg revealed sharp equilibration for GTP-Mg²⁺ and GMPPNP-Mg²⁺ nucleotide bound systems. Investigating internal variations through RMSF and cluster analyses helps us to identify the functionally important regions and nucleotide driven conformational variations that may stabilize/destabilize the RbgA-ribosome association. In addition, the construction and analyses of the dynamical protein contact network from the simulated trajectory reveal the nucleotide dependent allosteric connections between the nucleotide binding site and the rRNA interacting residues. Furthermore, the visualization followed by the dynamical distance calculations exhibited the possible role of Mg²⁺ in assisting GTP hydrolysis, such as (i) positioning the Asp150 of the switch-I (Sw-I) loop residue in a catalytically feasible configuration and (ii) stabilizing the solvated water molecules at the active-site through Mg²⁺ coordination. The results of our study can be used to design better chemical agents to regulate ribosome biogenesis through modulation of the function of the RbgA.

Methicillin-resistant Staphylococcus aureus (MRSA), a major cause of fatalities due to Antimicrobial Resistance (AMR), can act as an opportunistic pathogen despite being part of the normal human flora. MRSA infections, such as skin infections, pneumonia, sepsis, and surgical site infections, have risen significantly, with bloodstream infection cases increasing from 21% in 2016 to 35% in 2020. This surge has prompted research into alternative treatments like nanomaterials, photodynamic therapy, antimicrobial peptides (AMPs), and essential oils (EOs). AMPs and EOs have shown higher success rates compared to other alternatives, gaining significant attention for their effectiveness against MRSA. In this perspective, we have created a database for peptides and EOs that have been discovered to treat MRSA. Manual data curation was done to get related information on each of the anti-MRSA EOs and AMPs from the PubMed articles. This led to the curation of 1789 peptides (1029 unique) and 863 EOs (671 unique) that have been reported against MRSA. This was followed by database creation and the development of tools for sequence analysis and determination of physiochemical properties. This resource has been named 'The Anti-MRSA Resource' or 'TAMRSAR' which we believe will aid in future drug development efforts to combat the diseases caused by MRSA. The database is accessible on any web browser at the URL: https://bblserver.org.in/tamrsar/.

The present study explores the conformational dynamics of the membrane protein of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) within the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) complex using an all-atomistic molecular dynamics simulation approach. Significant structural changes were observed in the N-terminal, C-terminal, transmembrane, and beta-sheet sandwich domains of the MERS-CoV membrane protein. This study also highlights the structural similarities between the MERS-CoV and the SARS-CoV-2 membrane proteins, particularly in how both exhibit a distinct kink in the transmembrane helix caused by aromatic residue-lipid interactions. A structural expansion below the transmembrane and above the beta-sheet sandwich domain within the dimer was observed in all the M-proteins. This site on the beta-sheet sandwich domains near the C-terminal end could serve as a potential drug-binding site. Notably, a stable helical structure was identified in the C-terminal domain of the MERS-CoV membrane protein, whereas a proper secondary structural conformation was not observed in the SARS-CoV-2 membrane protein. Further, the SARS-CoV-2 membrane protein exhibited stronger binding to the lipid bilayer than the MERS-CoV, indicating its greater structural stability within the ERGIC complex. The structural similarity between the membrane protein of MERS-CoV and SARS-CoV-2 suggests the feasibility of employing a common inhibitor against these beta-coronaviruses. Furthermore, this analysis enhances our understanding of the membrane protein's interactions with proteins and lipids, paving the way for therapeutic developments against these viruses.

The COVID-19 pandemic posed a threat to global society. Delta and Omicron are concerning variants due to the risk of increasing human-to-human transmissibility and immune evasion. This study aims to evaluate the binding ability of these variants toward the angiotensin-converting enzyme 2 receptor and antibodies using a computational approach. The receptor-binding domain (RBD) of the two variants was created by CHARMM-GUI and then docked to the hACE2 receptor and two antibodies (REGN10933 and REGN10987). These complexes were also subjected to molecular dynamics simulation within 100 ns. As a result, the two variants, Omicron and Delta, exhibited stronger interaction with the hACE2 receptor than the wild type. The mutations in the RBD region also facilitated the virus's escape from antibody neutralization.

Four organotin(IV) carboxylate complexes; (C₄H₉)₃SnL (1), CH₃SnL (2), (C₄H₉)₂SnL₂ (3) and (CH₃)₂SnL₂ (4) are synthesized by the condensation reaction of organotin(IV) chlorides with sodium-4-chloro-2-methylphenoxyacetate (NaL). The FT-IR spectra suggested bridging/chelating bidentate coordination of the ligand to the tin atom. Single-crystal XRD analysis authenticated the FT-IR findings for 1 and 2. The NMR study has shown no significant differences in the signals of the free and coordinated ligand except for absence of a proton and up-filed/down-field shift of the C signal of the carboxyl group in the spectra. Complexes 1-4 have shown better enzyme inhibition, antioxidant, antimicrobial, and anticancer activities compared to the free ligand acid. Complex 3 was the most active inhibitor of AChE, BChE, α-glucosidase and α-amylase with IC₅₀ values of 43.76, 102.39, 232.71 and 91.84 µg/mL, respectively. Additionally, 3 with IC₅₀ values of 7.52 and 8.77 µg/mL in the DPPH and ABTS assays, respectively was better antioxidant than the standard. Complex 4 was the most efficient inhibitor of MAO-B and COX-2 enzymes with IC₅₀ values of 106.99 and 12.98 µg/mL, respectively, while 1 (IC₅₀ = 38.97 µg/mL) has shown the highest 5-LOX inhibition potential. Complexes 1-4 with IC₅₀ values in the range 237.51-168.35 µg/mL have shown better antileishmanial activity than HL (IC₅₀ = 277.57 µg/mL). The compounds showed good to potent antiproliferative activity in malignant glioma U87 cells with IC₅₀ values in the range 12.54 ± 0.05 to 37.65 ± 0.04 µg/mL. Antimicrobial activities have shown promising results for the compounds compared to the standards in some cases.

Cryptosporidiosis is an infection induced by the single-celled protozoan Cryptosporidium parasite. This parasite commonly infects the intestines of humans and animals, leading to gastrointestinal symptoms such as diarrhea, stomach cramps, nausea, and vomiting. Cryptopain protein, a type of cysteine protease found in the genome of Cryptosporidium parvum plays an important role in cell invasion and its survival. In this study, we mainly focused on the structural validation and reliability of docking aspects of the Cryptopain protein of C. parvum. The best-modeled structure of Cryptopain protein was run in a water environment through a 200 ns Molecular Dynamics (MD) simulation study. We employed a covalent docking scheme to screen suitable inhibitors against our target protein. Furthermore, the reliability of the binding mode for the best possible inhibitors was validated at a 100 ns time frame through a complex MD simulation study. From docking and simulation studies, we found Z3952175270 as a possible inhibitor on the basis of docking score and binding affinity for the possible binding site in the Cryptopain protein. Our findings highlight the potential of targeting Cryptopain protein with specific inhibitors, which could pave the way for the development of novel therapeutic strategies against cryptosporidiosis. This work contributes to the field by providing a deeper understanding of the molecular interactions involved in Cryptopain inhibition, potentially leading to effective treatments for a disease that significantly impacts public health, particularly in immunocompromised individuals and in areas with limited access to clean water.

Rice blast disease, instigated by Magnaporthe oryzae (M. oryzae), significantly impedes global rice production. Targeting the M. oryzae signaling protein, cAMP-Protein Kinase A (CPKA), which facilitates appressorium development and host penetration, this study explores the potential inhibitory effects of natural compounds. Virtual screening, molecular docking and text mining approaches were used to find the nimonol and curcumin that inhibit the CPKA protein. The MM-PBSA method was used to do the molecular dynamics (MD) simulation and the binding free energy analysis of the molecule. Their binding free energies (ΔG_bind) of -78.81 kJ/mol and -117.65 kJ/mol, respectively, point to the potential efficacy of the CPKA-nimonol and CPKA-curcumin complexes as inhibitors. The inhibitory effects have been further verified by various MD analysis. This study emphasizes the need to conduct further study on the CPKA protein and gives important insights into the possibility of natural compounds as M. oryzae inhibitors.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

F. carica is a small tree and commonly used as a traditional medicine against several disorders. Diabetes is currently treated with insulin and oral hypoglycemic medicines such as sulphonyl urea derivatives, bigunides, thiazolidinediones and alpha-glucosidase inhibitors. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists were found to be very much beneficial in the management of diabetes by inhibiting hepatic gluconeogenesis. The aim of this study is to evaluate the bioactive phytoconstituents from Ficus carica Linn. against the target PPAR-γ agonist by in silico docking approach. We investigated 68 phytoconstituents as potential inhibitors of PPAR-γ agonists and the top 24 phytoconstituents were further selected for molecular docking studies. Drug ability, side effects, and ADMET analysis were determined by using MolSoft, toxtree freeware, and ADMET SAR web server, respectively. The phytoconstituents were docked with the target PPAR-γ (PDB ID: 4Y29, 1.98 Å) receptor. Quercetin-3-o-rutinoside possessed the highest G score -14.22 kcal/mol, followed by Angelicin with a G score of -13.56 kcal/mol. All the other phytoconstituents displayed good pharmacokinetic and toxicological parameters with values within the permissible limits. The ligand-protein interaction was calculated by molecular dynamic (MD) simulation study. Subsequently, the binding free energy of the Quercetin-3-o-rutinosideand Pioglitazone complex was calculated using MMPBSA analysis. The results indicated that some of the phytoconstituents from Ficus carica have potency as an anti-diabetic agents. So, these bioactive phytoconstituents like Quercetin-3-o-glucoside, 5-O-caffeoylquinic acids may act as a good agonist for PPAR-γ.Communicated by Ramaswamy H. Sarma.