Journal of Biomolecular Structure & Dynamics最新文献

The main aim of this study is to address the global health crisis posed by tuberculosis (TB) through the exploration of novel therapeutic strategies targeting Mycobacterial phosphoribosyl pyrophosphate synthetase (MtPrsA), an untried enzyme involved in essential metabolic pathways of Mycobacterium tuberculosis. This enzyme plays a crucial role in cell wall synthesis, nucleotide biosynthesis and amino acid synthesis in M tb. Any hindrance to these may affect the growth and survival of the organism. Phytochemicals were systematically screened for potential inhibitors to MtPrsA. Subsequently, based on molecular docking studies, three compounds, namely, hesperidin, rebaudiosideA and rutin were selected. The binding stabilities of these compounds were analyzed using molecular dynamics simulation. Based on the RMSD score obtained, the binding stability of the compounds was confirmed. To validate the findings, an enzyme inhibition assay was done using recombinant MtPrsA. Ligation Independent Cloning (LIC cloning) method was used to produce recombinant His-tagged MtPrsA, followed by purification using Histrap columns. Enzyme kinetic studies unveiled the distinct modes of inhibition exhibited by each compound towards MtPrsA. RebaudiosideA and rutin emerged as competitive inhibitors, while hesperidin showcased a mixed inhibition profile. In conclusion, the study contributes valuable insights into potential therapeutic strategies for TB, through the exploration of alternative enzyme targets and the identification of phytochemical inhibitors. Notably, todate, no effective plant compounds have been reported as inhibitors to MtPrsA.

Adansonia digitata extracts are well known for their wide range of nutritional and medicinal benefits, including anti-diabetic, anti-inflammatory, antioxidant, and anti-cancerous properties. Yet, its efficacy against breast cancer has not been well-studied so far. Hence this study aims to investigate the anti-cancer properties of phytochemicals from the bark extract of the Adansonia digitata tree against BBOX1, a protein that stimulates the growth of Triple Negative Breast Cancer (TNBC) cells. TNBC is a highly aggressive and fatal form of cancer with limited therapeutic options available. By incorporating computational bioinformatics including Molecular docking, MMGBSA/PBSA, Molecular dynamics, and PCA/FEL analysis, the phytocompounds were scrutinized against BBOX1. Among 274 Phytocompounds only 37 compounds with good pharmacokinetic profiles based on ADME analysis were selected and docked with BBOX1. Of these compounds, the top 6 phytocompounds (CID_22217550, CID_559476, CID_6423866, CID_595387, CID_550931, and CID_559495) demonstrated good binding affinity, with better docking scores ranging from -8.599 to -7.207 kcal/mol respectively. Furthermore, based on MM/GBSA, Interaction profiling, and DFT analysis, only three phytocompounds namely CID_22217550, CID_559476, and CID_550931 were found to interact with the key residues such as Tyr_177, Trp_181, Asp_191, and Tyr_366 with better binding efficacy. In addition, these compounds were also observed to have the least RMS deviations with stable H-bond interactions maintained throughout the MD production run. Henceforth, the overall analysis infers that the phytocompounds CID_22217550, CID_559476, and CID_550931 shall act as potent inhibitors of BBOX1. However, their inhibitory efficacy has be to analyzed with further in vitro and in vivo analysis.

Ten novel 1,2,3,4-tetrahydroquinolone-triazole compounds (denoted as 6a-6j) were synthesized using click chemistry. These compounds were thoroughly characterized using various analytical techniques, such as FT-IR, mass spectrometry,¹H NMR, and ¹³C NMR. To gather a deeper understanding regarding structural properties of the synthesized compounds, we conducted Density Functional Theory (DFT) studies employing the B3LYP/6-311G (d,p) methodology. These calculations allowed us to evaluate important properties such as the HOMO-LUMO energy gap, chemical potential (µ), electrophilicity (ω), chemical hardness (η), dipole moment (Debye), and total energy (a.u.) for the synthesized hybrids. Moving on to the practical application of these hybrids, we evaluated in vitro antimicrobial inhibitory potential against two gram-positive and two gram-negative strains, and three fungal strains. Obtained outcomes revealed a range of antibacterial activity, with some compounds exhibiting excellent to moderate efficacy. Compounds 6b and 6i showed a very good result with a MIC of 12.5 μg/mL compared to standard Ciprofloxacin (MIC 25 μg/mL), demonstrating strong antibacterial activity against E. coli among the 6a-6j compounds. Furthermore, in silico docking validated our compounds' interaction with E. coli DNA gyrase B. Further, a 200 ns simulation revealed that the promising compounds maintained stability within the binding cavity, with RMSD values below 3 Å, and exhibited reduced structural fluctuations compared to the Apo protein, as evidenced by lower average RMSF values in the ligand-protein complexes. Additionally, an in silico ADME study assessed the drug-likeness of the hybrids, offering insights for future drug development.

The current study investigated five lichen-derived compounds and their hyaluronic acid (HA) conjugates for activity against five key cervical cancer targets. The lichen compounds and the reference drug topotecan exhibited docking scores ranging from -5.5 to -10.1 kcal/mol and -6.4 to -8.5 kcal/mol, respectively. Notably, the HA-evernic acid conjugate demonstrated the strongest binding to BCL-2 (-10.1 kcal/mol), forming two hydrogen bonds (Ala97, Glu133) and four hydrophobic interactions (Asp100, Arg143, Val145, Tyr199). Similarly, the HA-salazinic acid conjugate displayed high affinity for histone deacetylase 6 (HDAC6; -9.9 kcal/mol). The top-performing compounds, fumarprotocetraric acid, salazinic acid, topotecan, and their HA conjugates, were advanced to computational validation. Pharmacokinetic analysis revealed that HA-salazinic acid (HA-SAL) possessed optimal ADMET properties, including 71.39% human intestinal absorption, no inhibition of cytochrome P450 enzymes or P-glycoprotein, and low toxicity in cardiac (hERG), hepatic, and aquatic models. Density functional theory (DFT) calculations highlighted the HA conjugates of fumarprotocetraric acid (HA-FUM) and salazinic acid as superior to topotecan, with HA-FUM showing the lowest energy gap (-0.1038 eV) and highest softness (19.2678 eV), indicative of enhanced reactivity. Molecular dynamics simulations further validated the stability of HA-salazinic acid-HDAC6 (PDB ID 3PHD) and HA-evernic acid-BCL-2 (PDB ID 4MAN) complexes, outperforming the standard drug hyaluronic acid conjugate. These results underscore the potential of lichen compound-HA conjugates, particularly fumarprotocetraric acid, salazinic acid, and evernic acid, as candidates for cervical cancer therapy. Further preclinical and clinical studies are warranted to evaluate their efficacy and safety for translational applications.

The Hepatitis C virus (HCV) is a small, enveloped virus characterized by a positive-sense single-stranded RNA belonging to the Flaviviridae family. It causes hepatitis C, which leads to liver inflammation. It manifests as both acute and chronic hepatitis, ranging from mild illness to life-threatening conditions, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. The NS5B RNA-dependent RNA polymerase (RdRp) protein plays a vital role in the replication of the hepatitis C virus as the main RNA-synthesizing enzyme. It is crucial for forming new viral RNA, making it an ideal target for antiviral drugs. Inhibiting NS5B can inhibit virus replication, potentially preventing severe liver diseases, including cancer. Scientists have mapped the structure of the NS5B RdRp, revealing how different inhibitors interact with it, guiding the creation of targeted drugs. Nigella sativa, known for diverse bioactive compounds, is now being explored for its potential to combat viruses. Our research aims to determine whether compounds extracted from Nigella sativa can inhibit the NS5B RdRp enzyme of HCV. Through advanced computational analysis and molecular docking, Nigella sativa's phytoconstituents were scrutinized for their ability to bind and potentially inhibit NS5B RdRp. Amentoflavone, Rutin, and Catechin were selected based on their pharmacokinetic and enzyme-binding properties, which prompted further examination. Thorough molecular dynamics simulations affirmed the formation of stable complexes between these molecules and NS5B RdRp and provided valuable information about their influence on the enzyme's structural stability. The findings suggest these compounds have potent inhibitory actions, highlighting them as potential natural medicinal options against hepatitis C.

Glycogen phosphorylase (GP), a glycosyltransferase protein, was the initial allosteric enzyme identified and has since undergone thorough characterization. GP regulates the intracellular metabolization of glycogen thereby regulating blood glucose levels. Any dysfunction in this process results in altered blood glucose levels, such as Diabetes Mellitus (DM). Anthraquinones isolated from Aloe sinkatana have been found to possess several medicinal benefits. In this study, in-vitro techniques and computational tools were utilized to study in-depth the potential of inhibiting effects of A. sinkatana anthraquinones on GP. Two anthraquinones were isolated for this purpose. Their structures were elucidated and the possible effect on phosphorylase activity was assessed via an enzyme inhibition assay, where both the compounds showed substantial inhibitory activity against GP. The minimal difference between HOMO and LUMO energy levels further supported their potential binding, in line with DFT results. The binding modes and interactions were further explored in detail using in-silico studies via molecular docking and MD simulation. Results revealed strong protein-ligand interactions with Asn284 and Glu382, indicating stability. The deviations (RMSD) and fluctuations (RMSF) remained consistent, with RMSD averaging 2.2Å and RMSF around 1.5 Å. Compounds A and B are effectively bound to the receptor's active site, with -58.63 and -59.65 kcal/mol binding free energies recorded, suggesting potent GP inhibition potential. QSAR analysis revealed positive Log P values, indicating their lipophilic nature, and adhered to Lipinski's rule of 5. In conclusion these anthraquinones showed strong potential in controlling chronically elevated blood sugar levels which could help in the management of DM.

Antimicrobial resistance is recognized as a major worldwide public health dilemma in the current century. Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, causes nosocomial infections like respiratory tract infections, urinary tract infections, dermatitis, and cystic fibrosis. It manifests antibiotic resistance via intrinsic, acquired, and adaptive pathways, where efflux pumps function in the extrusion of antibiotics from the cell. MexB protein, part of the tripartite efflux pumps MexAB-OprM present in P.aeruginosa, expels the penems and β-lactam antibiotics, thereby enhancing Pseudomonas resistance. The current study was intended to screen around 1602 clinically approved drugs to understand their ability to inhibit the MexB protein. Amongst them, the top 5 drug molecules were selected based on the binding energies for analyzing their physio-chemical and toxicity properties. Lomitapide was found to have the maximum negative binding energy followed by Nilotinib, whereas Nilotinib's number of hydrogen bonds was higher than that of Lomitapide. ADMET study revealed that all 5 drug molecules had limited solubility. Also, Lomitapide and Venetoclax showed low bioavailability scores, while Nilotinib, Eltrombopag, and Conivaptan demonstrated higher potential for therapeutic levels. A molecular dynamic simulation study of the 5 drugs against MexB was carried out for 200 nanoseconds. The RMSD, RMSF, Hydrogen bond formation, Radius of gyration, SASA, PCA, DCCM, DSSP and MM-PBSA binding energy calculation along with demonstrated high stability of the MexB-Nilotinib complex with lesser distortions. Our study concludes, that Nilotinib is a potential inhibitor and can be developed as a therapeutic agent against MexB protein for controlling P. aeruginosa infections.

Bioactive metabolites from Linum usitatissimum L. have been extensively explored for their anti-cancer and antioxidant potential in several cancer cell lines. The bioactive chemicals that have been reported are being assessed using in silico methods to create a new antagonist that may effectively target hepatocellular carcinoma by inhibiting c-Kit (stem cell factor receptor) and HBXIP (hepatitis B X-interacting protein). Dysregulation in function or overexpression of c-Kit and HBXIP shows the development of hepatocellular carcinoma. The objective of this study is to use computational approaches to choose the most suitable candidate that interacts with our chosen target proteins, c-Kit and HBXIP, derived from flaxseed. From the online resources, namely RCSB and PubChem, the 3D structures of the proteins and bioactive compounds are obtained. The drug likeness study and ADMET profiling of these bioactive compounds were performed, and the selected fourteen compounds were considered for docking analysis. The molecular docking study revealed that secoisolariciresinol (SECO) has a comparable interaction affinity of -5.5 kcal/mol and -7.5 kcal/mol with HBXIP and c-KIT, respectively, when compared to the redock co-crystal complex (-3.5 kcal/mol and -12.4 kcal/mol, respectively). The results of the molecular dynamics simulation study demonstrate the constancy of the SECO_HBXIP and SECO_c-Kit complexes when compared to the redock complex. The average root-mean-square fluctuation (RMSF), root-mean-square deviation (RMSD) values, gyration (Rg) and hydrogen bonding provide additional evidence of the significant binding and stability of the complexes. Moreover, in vitro cell viability assay on HepG₂ also showed a significant reduction in the cell proliferation after the treatment with SECO.

In this study, we designed, synthesized and evaluated some novel imidazo[1,2-a]pyridine derivatives as potential anti-TB agents. Preliminary in vitro screening for anti-TB activity of the synthesized compounds was performed against H37Rv strain using the microplate Alamar Blue assay (MABA). Network pharmacology was used to identify the possible targets and pathways of these compounds against Mtb infection. Molecular docking and molecular dynamics simulations were also performed to investigate the binding modes and stability of these compounds with the selected targets. The results showed that some of the synthesized compounds (6b, 6c, 6e, 6f, 6h, 6i, 6j, 6n and 6o) exhibited potent anti-TB activity, with minimum inhibitory concentrations (MICs) ranging from 1.6 to 6.25 μg/mL. The network pharmacology analysis revealed that among the 455 putative targets of imidazo[1,2-a]pyridine derivatives, 24 targets are the potential targets for treatment of Mtb infection. Among these 24 targets, 10 hub-targets were identified (TLR4, ICAM1, TLR9, STAT3, TNFRSF1A, ERBB2, CXCR3, ACE, IKBKG and NOS2) which were significantly involved in GO processes such as positive regulation of DNA-binding transcription factor activity, peptidyl-tyrosine phosphorylation, positive regulation of inflammatory response, mononuclear cell proliferation, regulation of hemopoiesis and cytokine production involved in inflammatory response and KEGG pathways such as pathways in Tuberculosis, NF-kappa B signalling, HIF-1 signalling PD-L1 expression, and PD-1 checkpoint pathway in cancer. Molecular docking and dynamics simulations confirmed the stable interactions of imidazo[1,2-a]pyridine derivatives with core target active sites, highlighting their potential as novel anti-TB drug candidates.

The emergence of highly contagious SARS-CoV-2 variants emphasizes the need for antiviral drugs that can adapt to evolving viral mutations. Despite widespread vaccination efforts, novel variants and recurrence cases raise concerns about COVID-19. Although repurposed drugs like Remdesivir, a nucleoside inhibitor, offer treatment, there is still a critical need for alternative drugs. Inhibiting viral RdRp function remains a key strategy. Structural analysis highlights the importance of pyrrolo-triazine and pyrimidine scaffolds in nucleoside inhibitors. Our study designed Peptide Nucleic Acid (PNA) antisense pronucleotides by combining these scaffolds using structure-guided drug design. Molecular modeling, including molecular docking, pharmacokinetics, molecular dynamics simulations, and MMPBSA binding energy calculations, predicts that modified PNAs can disrupt ribosome assembly at the RdRp translation start site. The neutral backbone of PNAs may enhance sequence-specific RNA binding. MD simulations revealed that complexes of Remdesivir and L14 remained stable throughout, with the phosphate tail of L14 stabilized by a positive amino acid pocket near the RdRp-RNA entry channel, similar to Remdesivir. Additionally, L14's guanine motif interacted with U20, A19, and U18 on the primer RNA strand. The lead PNA analog (L14) showed superior binding free energy to both RdRp (-47.26 kcal/mol) and RdRp-RNA (-85.66 kcal/mol), outperforming Remdesivir. Key amino acid residues critical for binding affinity were identified, providing valuable insights for drug development. This promising PNA-mimetic compound offers dual-target specificity, presenting a compelling avenue for developing potent anti-SARS-CoV-2 agents.