Journal of Biomolecular Structure & Dynamics最新文献

Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on the mucosal epithelium, is the most common oral malignancy. About 10% of cancer patients within the Indian subcontinent suffer from OSCC, primarily due to chewing of betel plant derivatives. Concomitant administration of the chemotherapeutic agent (Cisplatin/Paclitaxel) is the treatment of choice. Analysis of the oral mycobiome of OSCC patients has projected the role of Candida albicans in potentiating OSCC. Hence, repurposing antifungal drugs emerges as a promising approach, as these drugs could target both the cancer cells and the infection. Cancer cells often have heightened energy requirements, and targeting mitochondrial proteins to disrupt mitochondrial division and induce dysfunction contributing to cell death, offers a method for treating OSCC. We identified 18 mitochondrial targets playing a crucial role in the maintenance of mitochondrial homeostasis. They were docked against 125 antifungal ligand molecules sourced from PUBCHEM. Ligand profiling was performed using Lipinski's rule of 5, SwissADME and ProTox. Also, molecular dynamics and MM-PBSA were performed to validate our results. Among all protein ligand interactions, we observed that targeting DRP1 with itraconazole yielded superior binding and stability. Overall, lower toxicity and thumping ADME properties solidified the choice of ligand. We hope this experimental approach will enable us to provide a basis for selecting a lead molecule for a possible novel nano-formulation and validate our finding through in-vitro cell line-based testing.

Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for attenuating oxidative stress through its ability to facilitate the dismutation of the superoxide radical into oxygen and hydrogen peroxide. The progressive loss of motor neurons characterize amyotrophic lateral sclerosis (ALS), a crippling neurodegenerative disease that is caused by mutations in the SOD1 gene. In this study, in silico mutational analysis was performed to study the various mutations, the pathogenicity and stability ΔΔG (binding free energy) of the variant of SOD1. x in the protein variant analysis showed a considerable destabilizing effect with a ΔΔG value of -4.2 kcal/mol, signifying a notable impact on protein stability. Molecular dynamics simulations were conducted on both wild-type and C146R mutant SOD1. RMSD profiles indicated that both maintained consistent structural conformation over time. Additionally, virtual screening of 3067 FDA-approved drugs against the mutant SOD1 identified two potential binders, Tucatinib (51039094) and Regorafenib (11167602), which interacted with Leu106, similar to the control drug, Ebselen. Further simulations assessed the dynamic properties of SOD1 in monomeric and dimeric forms while bound to these compounds. 11167602 maintained stable interaction with the monomeric SOD1 mutant, whereas 51039094 and Ebselen dissociated from the monomeric protein's binding site. However, all three compounds were stably bound to the dimeric SOD1. MM/GBSA analysis revealed similar negative binding free energies for 11167602 and 51039094, identifying them as strong binders due to their interaction with Cys111. Experimental validation, including in vitro, cell-based, and in vivo assays are essential to confirm these candidates before advancing to clinical trials.

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.