Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa). The antagonistic drugs, which suppress the activity of AR, are widely used in the treatment of PCa. However, ...the molecular mechanism of antagonism about how ligands affect the structures of AR remains elusive. To better understand the conformational variability of ARs bound with agonists or antagonists, we performed long time unbiased molecular dynamics (MD) simulations and enhanced sampling simulations for the ligand binding domain of AR (AR-LBD) in complex with various ligands. Based on the simulation results, we proposed an allosteric pathway linking ligands and helix 12 (H12) of AR-LBD, which involves the interactions among the ligands and the residues W741, H874, and I899. The interaction pathway provides an atomistic explanation of how ligands affect the structure of AR-LBD. A repositioning of H12 was observed, but it is facilitated by the C-terminal of H12, instead of by the loop between helix 11 (H11) and H12. The bias-exchange metadynamics simulations further demonstrated the above observations. More importantly, the free energy profiles constructed by the enhanced sampling simulations revealed the transition process between the antagonistic form and agonistic form of AR-LBD. Our results would be helpful for the design of more efficient antagonists of AR to combat PCa.
The outbreak and high speed global spread of the new strain of influenza A/H1N1 virus in 2009 posed a serious threat to global health. It is more likely that drug-resistant influenza strains will ...arise after the extensive use of anti-influenza drugs. Consequently, the identification of the potential resistant sites for drugs in advance and the understanding of the corresponding molecular mechanisms that cause drug resistance are quite important in the design of new drug candidates with better potency to combat drug resistance. Here, we performed molecular simulations to evaluate the potency of oseltamivir to combat drug resistance caused by the mutations in 2009 A/H1N1 neuraminidase (NA). We examined three representative drug-resistant mutations in NA, consisting of H274Y, N294S, and Y252H. First, a theoretical structure of A/H1N1 NA in complex with oseltamivir was constructed using homology modeling. Then, molecular dynamics (MD) simulations, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) calculations, and MM/GBSA free energy decomposition were used to characterize the binding of oseltamivir with the wild type (WT) and three mutated NAs. Our predictions show that N294S and H274Y, two popular drug-resistant mutations in different variants of NA, still cause significant resistance to oseltamivir. However, the Y252H mutation does not impair the interactions between oseltamivir and A/H1N1 NA. An examination of individual energy components shows that the loss of polar interactions is the key source for the resistance of the studied mutations to oseltamivir. Moreover, free energy decomposition analysis and structural analysis reveal that the N294S or H274Y mutation triggers the large-scale conformational changes of the binding pocket and then impairs the affinity of oseltamivir. We expect that our results will be useful for the rational design of NA inhibitors with high potency against drug-resistant A/H1N1 mutants.
Nanoscale particles have become promising materials in many fields, such as cancer therapeutics, diagnosis, imaging, drug delivery, catalysis, as well as biosensors. In order to stimulate and ...facilitate these applications, there is an urgent need for the understanding of the interaction mode between the nano-particles and proteins. In this study, we investigate the orientation and adsorption between several enzymes (cytochrome c, RNase A, lysozyme) and 4 nm/11 nm silica nanoparticles (SNPs) by using molecular dynamics (MD) simulation. Our results show that three enzymes are adsorbed onto the surfaces of both 4 nm and 11 nm SNPs during our MD simulations and the small SNPs induce greater structural stabilization. The active site of cytochrome c is far away from the surface of 4 nm SNPs, while it is adsorbed onto the surface of 11 nm SNPs. We also explore the influences of different groups (-OH, -COOH, -NH2 and CH3) coated onto silica nanoparticles, which show significantly different impacts. Our molecular dynamics results indicate the selective interaction between silicon nanoparticles and enzymes, which is consistent with experimental results. Our study provides useful guides for designing/modifying nanomaterials to interact with proteins for their bio-applications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding ...domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR–coactivator interactions. In this work, the effects of the ligand binding on the AR–coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.
An evolving family of mobile colistin resistance (MCR) enzymes is threatening public health. However, the molecular mechanism by which the MCR enzyme as a rare member of lipid A-phosphoethanolamine ...(PEA) transferases gains the ability to confer phenotypic colistin resistance remains enigmatic. Here, we report an unusual example that genetic duplication and amplification produce a functional variant (Ah762) of MCR-3 in certain Aeromonas species. The lipid A-binding cavity of Ah762 is functionally defined. Intriguingly, we locate a hinge linker of Ah762 (termed Linker 59) that determines the MCR. Genetic and biochemical characterization reveals that Linker 59 behaves as a facilitator to render inactive MCR variants to regain the ability of colistin resistance. Along with molecular dynamics (MD) simulation, isothermal titration calorimetry (ITC) suggests that this facilitator guarantees the formation of substrate phosphatidylethanolamine (PE)-accessible pocket within MCR-3-like enzymes. Therefore, our finding defines an MCR-3 inside facilitator for colistin resistance.
Display omitted
•The lipid A pocket is illustrated in EptA and Ah762•The MCR-3 inside Linker 59 acts as a facilitator to govern its enzymatic action•The facilitator allows binding of MCR to lipid PE, its first substrate•Linker 59 is a sufficient (rather than prerequisite) element for MCR colistin resistance
Xu et al. define a hinge-like linker from the prevalent MCR-3 colistin resistance enzyme, which facilitates enzymatic action and phenotypic resistance. The facilitator represents an alternative drug target for small molecules reversing antibiotic resistance.
Structure-based drug design depends on the detailed knowledge of the three-dimensional (3D) structures of protein–ligand binding complexes, but accurate prediction of ligand-binding poses is still a ...major challenge for molecular docking due to deficiency of scoring functions (SFs) and ignorance of protein flexibility upon ligand binding. In this study, based on a cross-docking dataset dedicatedly constructed from the PDBbind database, we developed several XGBoost-trained classifiers to discriminate the near-native binding poses from decoys, and systematically assessed their performance with/without the involvement of the cross-docked poses in the training/test sets. The calculation results illustrate that using Extended Connectivity Interaction Features (ECIF), Vina energy terms and docking pose ranks as the features can achieve the best performance, according to the validation through the random splitting or refined-core splitting and the testing on the re-docked or cross-docked poses. Besides, it is found that, despite the significant decrease of the performance for the threefold clustered cross-validation, the inclusion of the Vina energy terms can effectively ensure the lower limit of the performance of the models and thus improve their generalization capability. Furthermore, our calculation results also highlight the importance of the incorporation of the cross-docked poses into the training of the SFs with wide application domain and high robustness for binding pose prediction. The source code and the newly-developed cross-docking datasets can be freely available at
https://github.com/sc8668/ml_pose_prediction
and
https://zenodo.org/record/5525936
, respectively, under an open-source license. We believe that our study may provide valuable guidance for the development and assessment of new machine learning-based SFs (MLSFs) for the predictions of protein–ligand binding poses.
•The structures and therapeutic importance of ROCK are outlined.•The available inhibitors of ROCK are summarized.•The binding mechanisms of representative ROCK inhibitors are represented.•The ...applications of molecular modeling in the design of ROCK inhibitors are discussed.
Rho-associated protein kinases (ROCK1 and ROCK2) belong to the AGC family of serine–threonine kinases, and regulate a wide range of fundamental cell functions. Inhibition of ROCK has been proven to be of potential therapeutic benefit for a variety of diseases. In this review, the structures and therapeutic importance of ROCK are discussed briefly. Then, the recent status of the development of ROCK inhibitors is also summarized. Our review offers a foundation outline from which strategies to design new leads against ROCK can be developed.
The field of drug delivery is advancing rapidly. By controlling the precise level and/or location of a given drug in the body, side effects are reduced, doses are lowered, and new therapies are ...possible. Nonetheless, substantial challenges remain for delivering specific drugs into specific cells. Computational methods to predict the binding and dynamics between drug molecule and its carrier are increasingly desirable to minimize the investment in drug design and development. Significant progress in computational simulation is making it possible to understand the mechanism of drug delivery. This review summarizes the computational methods and progress of four categories of drug delivery systems: dendrimers, polymer micelle, liposome and carbon nanotubes. Computational simulations are particularly valuable in designing better drug carriers and addressing issues that are difficult to be explored by laboratory experiments, such as diffusion, dynamics, etc.
Cullin-RING E3 ligase (CRL) is the largest family of E3 ubiquitin ligase, responsible for ubiquitylation of ∼20% of cellular proteins. CRL plays an important role in many biological processes, ...particularly in cancers due to abnormal activation. CRL activation requires neddylation, an enzymatic cascade transferring small ubiquitin-like protein NEDD8 to a conserved lysine residue on cullin proteins. Recent studies have validated that neddylation is an attractive anticancer target. In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylation in a variety of cancer cell lines and selectively caused accumulation of NOXA and MCL1, the substrates of CUL5 and CUL1, respectively, in multiple cancer cell lines. Combination of gossypol with specific MCL1 inhibitor synergistically suppress growth of human cancer cells. Our study revealed a previously unknown anti-cancer mechanism of gossypol with potential to develop a new class of neddylation inhibitors.
In this study, we developed and evaluated a novel parallel virtual screening strategy by integrating molecular docking and complex-based pharmacophore searching based on multiple protein structures. ...First, the capacity of molecular docking or pharmacophore searching based on any single structure from nine crystallographic structures of Rho kinase 1 (ROCK1) to distinguish the known ROCK1 inhibitors from noninhibitors was evaluated systematically. Then, the naı̈ve Bayesian classification or recursive partitioning technique was employed to integrate the predictions from molecular docking and complex-based pharmacophore searching based on multiple crystallographic structures of ROCK1, and the integrated protocol yields much better performance than molecular docking or complex-based pharmacophore searching based on any single ROCK1 structure. Finally, the well-validated integrated virtual screening protocol was applied to identify potential inhibitors of ROCK1 from traditional chinese medicine (TCM). The obtained potential active compounds from TCM are structurally novel and diverse compared with the known inhibitors of ROCK1, and they may afford valuable clues for the development of potent ROCK1 inhibitors.
PDF
