Journal of Biomolecular Structure & Dynamics最新文献

From the most prevalent cancers, breast and lung cancers have a meager survival rate for both men and women. These two cancers are related to each other. Breast cancer can possibly spread to the lungs or the region between the lung and the chest wall. The organic heterocyclic compounds are expected to possess some anti-cancerous properties. Hence, this study is to investigate the molecular characteristics of the derivatives of alkyl-5-hydroxy-7-aryl-5-methyl-1,3-dioxo-2-phenyl hexahydropyrazolo[1,2a] (Asif, 2017; Hei et al., 1996; Kumar et al., 2013) triazole-6-carboxylate and the drugability of these compounds have also been examined against estrogen receptor (ER) mutant L536S, which causes ER-positive breast cancer, and anaplastic lymphoma kinase responsible for non-small cell lung cancer (NSCLC). DFT and TDDFT have been used to study all the derivatives with B3LYP/6-311++G(d, p) basis set. Substituent effects via ¹H NMR,¹³C NMR, IR, UV and HOMO-LUMO energy gaps of -CH₃, -F, -Cl, -Br, -I, -NO₂, and -SO₃H groups at the para positions of 7-aryl substituent present in triazole compound have been studied. The global reactivity of these compounds is also being discussed in terms of band gap (E_HOMO-E_LUMO). The NTO analysis monitors and characterizes the direction and nature of charge transfer. The drug-likeness using Lipinski's Rule of Five, followed by molecular docking of the compounds with the target proteins have also been studied. Molecular dynamics simulations and free energy calculations were conducted for all protein-ligand complexes to predict potential inhibitors targeting the proteins.

The Nipah virus (NiV), a highly pathogenic zoonotic virus of the Paramyxoviridae family, poses significant threats with its alarming mortality rates and pandemic potential. Despite historical cases, effective therapeutics remain elusive, prompting urgent exploration of potential antivirals. In this study, a structure-based virtual screening approach was employed to evaluate 690 metabolites sourced from ten medicinal plants (Allium sativum, Andrographis paniculata, Cocos nucifera, Euphorbia hirta, Euphorbia neriifolia, Moringa oreifera, Ocimum basilicum, Piper nigrum, Vitex negundo, and Zingiber officinale) for their antiviral activity against Nipah virus proteins. Through targeted and blind docking experiments, forty-three (43) compounds were found to exhibit high binding affinities (≤ -8 Kcal mol^-1) and validated site-specificity. Subsequent analysis of the ADMET properties of these compounds, along with off-target docking to swine receptors, six (6) compounds with profiles akin to approved drugs and minimal off-target binding were identified. Stability screening via 100 ns and 300 ns molecular dynamics simulations identified two (2) of the six compounds that demonstrated sustained dynamic stability over an extended duration, coupled with favorable binding energies from MM-(GB/PB)SA calculations and biologically significant binding modes and residue interactions. Betulinic acid and CID 118716357 exhibited significant potential as inhibitors of Nipah virus fusion (F) glycoprotein trimer by targeting the oligomerization sites used to form the functional hexamer-of-trimer assembly. Coupled with their dynamic stability and favorable ADMET profiles in both human and swine conditions, these findings make them good candidates for subsequent in vitro testing and further biological screening in the quest for potent antiviral drugs targeting Nipah virus proteins.

Transthyretin (TTR) is a vertebrate-exclusive transport protein that plays a key role in binding and distributing thyroid hormones. However, its evolutionary origin lies in the duplication of the gene that encoding the enzyme 5-hydroxyisourate hydrolase (HIUase), which is involved in uric acid metabolism. Unlike TTR, HIUase is ubiquitous in both prokaryotes and eukaryotes, with the exception of hominids. Both HIUase and TTR subfamilies form homotetramers, possessing an internal charged cavity between the two dimer pairs. Based on their high degree of structural similarity, we hypothesized that specific in silico substitutions would enable the interconversion between these protein functions. Using an evolution-based approach, we engineered two putative protein sequences, where correlated locally conserved positions from one subfamily representative sequence were substituted by the other, and vice versa. Applying computational modeling techniques, the best models were refined, validated, and their cavity volumes, three-dimensional geometries, propensity to aggregation and electrostatic potentials were analyzed. Molecular dynamics simulations were performed with the reference proteins and the engineered mutants in the bound and unbound states. We demonstrate that the volumes and geometries differ from one another, due to size and physicochemical differences between their ligands. The bound state mutant complexes are stable, and the enzymatic assay demonstrated active new enzymes. Our work suggests that the evolution-based protein engineering approach used has residue-specific resolution to identify locally conserved residues in the sequence of evolutionarily related proteins, such as HIUase and TTR.

UDP-N-acetylenolpyruvoylglucosamine reductase (Mur B) from Mycobacterium tuberculosis has gathered significant pharmaceutical interest as a pivotal target because of its essential role in bacterial viability. This study employed computational methods to screen and assess the inhibitory potential of dicoumarol derivatives against the Mur B protein. A diverse set of dicoumarols, sourced from PubChem and Zinc database, is subjected to molecular docking, ADME studies, and MD simulations to elucidate interacting modes and stability. A QSAR model was constructed for dicoumarol derivatives based on known inhibitor MIC values against Staphylococcus aureus and Mur B. The four best dicoumarols (CID142097979, CID54716867, CID91962283, CID54705236) aligned well with the model. Subsequently, these dicoumarols were scrutinized via 200 ns MD simulations and MM-PBSA analysis to assess their complex stability with Mur B protein. Various MD simulation parameters such as RMSD, RMSF, Rg, H-bonds, PCA, and FEL were employed. The 200 ns MD simulation analysis outcomes indicated that the Mur B-CID54705236 complex exhibited the highest stability and possessed the binding energy of -59.96 kcal/mol further verifying its stability. The post-dynamic simulation analysis showed four hydrogen bond formations with Ser70, Asn71, Leu72 and Gln137 residues at the active site of Mur B. Overall, these results underscored dicoumarol derivatives as potential Mur B inhibitors and these findings can serve as a basis for further in vitro studies against Mur B protein.

In our preliminary in vitro studies, the Enhydra fluctuans extract demonstrated inhibition of calcium phosphate (brushite) crystals. Human serum albumin (HSA) is known to act as a promoter of brushite crystal growth. Therefore, the present study aims to explore the molecular mechanisms involved in brushite crystal nephrolithiasis by conducting molecular docking of phytoconstituents from E. fluctuans with HSA. Molecular docking is conducted on 35 phytoconstituents of E. fluctuans against HSA, and the top five compounds are further analyzed using Induced Fit Docking (IFD) and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) methods. Molecular dynamics simulations for 50 ns are performed to assess the stability of the protein-ligand complexes. Additionally, in silico physicochemical; absorption, distribution, metabolism, excretion, and toxicity (ADME/T); and pharmacophore modeling studies are conducted. The binding pocket analysis identifies potential binding sites on HSA, and molecular docking reveals Baicalein-7-o-glucoside as the top-performing compound with a strong binding affinity. IFD and MM-GBSA support the stability of the complex. Molecular dynamics simulations indicate stable interactions over the 50 ns period. In silico ADME/T studies suggest that the top five phytoconstituents exhibit drug-like properties with satisfactory pharmacokinetic profiles. Pharmacophore modeling generates a three-point hypothesis, and its validation indicates suitability for the HSA-Baicalein-7-O-glucoside complex. The findings from the current computational investigations indicate that polyphenolic phytoconstituents of E. fluctuans containing the 5,6-dihydroxy chromone ring, such as Baicalein-7-O-diglucoside, may modulate the activity of HSA (PDB ID: 1E7H), potentially inhibiting the process of crystallization.

Senna (Cassia angustifolia Vahl.) is an important medicinal plant used in traditional and modern systems medicine to manage constipation. While various treatment strategies exist, there is growing interest in utilizing traditional herbal medicines like Indian Senna as a natural alternative. Though Isopentenyl Diphosphate Delta-Isomerase (IDI) has been proven to be one of the key enzymes in the sennoside biosynthesis pathway, characterization of it remains largely unexplored. This study aims to bridge the knowledge gap by investigating IDI, an important enzyme involved in sennoside biosynthesis in plants. The study retrieved the coding DNA sequence (CDS) of IDI from Senna transcriptome and successfully cloned and sequenced the gene. Physicochemical properties and secondary structure analysis unveiled protein characteristics, while homology modelling and molecular docking of DMAPP and IPP ligands assessed binding patterns and interactions with caIDI. Notably, Lys37, Arg72, Lys76, Cys88, Ser89, His90, and Lys113 residues engaged with DMAPP, and Arg72, Lys76, Lys113, Ser89, and His90 residues interacted with IPP. Molecular dynamics simulations affirmed protein-ligand complex stability. IPP established sustained hydrogen bonds with Arg72, Ser89, and Lys113; DMAPP sustained interactions with Lys37, Arg72, Ser89, His90 and Lys113. His41, Glu148, Glu150 engaged with magnesium ion; Val77, Thr78 showed dual interactions with IPP, indicating its substrate binding roles. These findings enhance IDI understanding in Indian Senna which not only plays vital role in isoprenoid biosynthesis but also anthraquinone biosynthesis like sennosides.

In about 85% of cancer malignancies, replicative immortality caused by increased telomerase activity makes it an attractive target for developing anticancer therapeutics. However, the lack of approved small-molecule inhibitors rooted in the structural ambiguity of telomerase has impeded drug development for decades. In this study, we have exploited the FVYL pocket in the thumb domain, which plays a key role in the enzyme's processivity. Due to the unavailability of a co-crystalized structure of BIBR1532 with the catalytic hTERT thumb domain, we utilized the molecular dynamics method to identify the precise binding site of the inhibitor. Two pharmacophore models were generated and validated for the putative (Site-I) and newly identified (Site-II) binding pockets which were screened virtually through the ChemDiv anticancer library, Otava drug-like green collection to identify novel lead compounds, and Binding database to screen out thumb domain-specific telomerase inhibitors. The top hits obtained were filtered using drug-likeliness parameters followed by redocking using a three-level screening strategy into their binding site. The structural investigation, molecular docking studies, and confirmatory molecular dynamics revealed that the exact binding site of BIBR1532 is away from the reported FVYL pocket with characteristic interactions conserved. Subsequently, the lead compounds with the highest docking scores and significant interactions in the newly discovered extended FVYL pocket were validated using 100 ns MD simulations. Additionally, cross-validated binding free energy calculations were performed using MM-PB(GB)SA methods followed by PCA and FEL characterization. The identified top lead compounds can be validated in vitro and taken forward for anticancer drug development.

Highly mutated HIV-1 protease (PR) compromises the efficacy of lopinavir (LPV) and darunavir (DRV) used to formulate salvage regimens in HIV/AIDS management. Here, we report the kinetics of inhibition of lopinavir (LPV) and darunavir (DRV) on highly mutated South African HIV-1 subtype C PR obtained from clinical isolates. The wild-type and mutant South African HIV-1 subtype C PR were cloned and purified. Enzyme inhibition assays and fluorescence spectroscopy were utilized to determine the binding kinetics of LPV and DRV with the wild-type and mutant HIV-1 PR variants. Like DRV, the results of this study show that LPV has a mixed-type inhibition mechanism, which indicates the possibility of a second binding site on HIV-1 PR. Both LPV and DRV poorly inhibited the highly mutated HIV-1 PR variants and had a markedly increased dissociation rate cons bound to the mutant variants compared to the wild type. The fast dissociation of these inhibitors translated into a short residence time of the inhibitor bound to the mutant HIV-1 PR variants. Fluorescent spectroscopy showed that the changes in the tertiary structure of the mutant HIV-1 PR variants were associated with a more open conformation. This open conformation was associated with altered conformational dynamics, which may have resulted in the loss of tight binding of LPV and DRV. This study's findings provide insight into the mechanism of resistance to LPV and DRV by highly mutated HIV-1 PR and provide information supporting the use of binding kinetics measurement in understanding HIV-1 PR inhibitor drug resistance evolution.

Pathogenesis and therapeutic drugs for ulcerative colitis (UC) have plagued researchers worldwide. In this study, therapeutic targets, and drugs from Chinese medicines for UC were screened using bioinformatics. We downloaded five datasets from the GEO database and three machine learning algorithms were used for screening diagnostic biomarkers of UC. Combined with the differential genes for UC, gene sets related to bile acid metabolism, short-chain fatty acids, apoptosis, pyroptosis, G-protein-coupled receptors, mitochondria, and autophagy were collected to screen the core targets, and analyze the association of therapeutic genes (diagnostic biomarkers and core targets) with immune cells. In addition, screening ingredients of Chinese medicines based on UC therapeutic targets was performed. Molecular docking, molecular dynamics simulation, and literature validation were also performed. The screening yielded 37 key therapeutic targets, including 5 diagnostic biomarkers (CCL11, CXCL1, PDZK1IP1, TIMP1, and UGT2A3) and 32 core targets based on hot gene sets. Immune cell infiltration was strongly associated with therapeutic targets in UC, especially neutrophils, macrophages, mast cells, and dendritic cells. Furthermore, a total of 33 compounds with high safety had been recognized as having potential to mitigate UC by reverse prediction from Chinese medicines, and molecular docking, molecular dynamics simulation, and literature reports preliminarily validated the screening results. Although further experimental validation is needed, this work provides some potential therapeutic targets and drugs from Chinese medicines against UC.