In Silico Study on the Interaction of Thiazolidinediones and β-Lactoglobulin by Molecular Dynamics and Docking Approach

Thiazolidinediones are widely used in the treatment of diabetes mellitus type 2. An investigation of their interaction with a transport protein, such as β-lactoglobulin (BLG), at the atomic level could be a valuable factor in controlling their transport to biological sites. The interaction of troglitazone, pioglitazone, and rosiglitazone, as representative thiazolidinediones, and BLG, as a transport protein, was investigated using molecular docking and molecular dynamics (MD) simulation methods. The molecular docking results showed that these thiazolidinediones bind to the internal cavity of BLG and the BLG affinity for binding the thiazolidinediones decreases in the following order: troglitazone > pioglitazone > rosiglitazone. The analysis of MD simulation trajectories showed that the BLG and BLG-thiazolidinedione complexes became stable at approximately 2500 ps and that there was little conformational change in the BLG-thiazolidinedione complexes over a 10 ns timescale. In addition, the profiles of atomic fluctuations showed the rigidity of the ligand-binding site during the simulation time.     

Computational Studies on the Interaction of Arctiin and Liquiritin With β-lactoglobulin

The study of the interaction of drugs purified from natural sources and a transport protein, such as β-lactoglobulin (BLG), at the atomic level could be a valuable factor to control their transport to biological sites. In the present study, molecular docking and molecular dynamics simulation methods were used to study the interaction of arctiin and liquiritin as natural drugs and BLG as the transport protein. The molecular docking results indicated that these drugs bind in the internal cavity of BLG and the BLG affinity for binding the liquiritin is greater than arctiin. The docking results also indicated that the hydrogen bond interactions have a dominant role in the BLG-drug complex stability. The analysis of MD simulation trajectories showed that the root mean square deviation (RMSD) of BLG-liquiritin, unliganded BLG, and BLG-arctiin reached equilibrium and fluctuated around the mean value at about 1000, 3500, and 4000 ps, respectively. The time evolution of the radius of gyration and total solvent accessible surface of the protein showed that BLG-arctiin and BLG-liquiritin complexes became stable around 2500 and 5000 ps, respectively. Also, the profiles of atomic fluctuations during the simulation showed the rigidity of the ligand binding sites.     

The Interaction of Polyphenol Flavonoids with β-lactoglobulin: Molecular Docking and Molecular Dynamics Simulation Studies

The interaction of quercetin, quercitrin, and rutin, as natural polyphenolic compounds, with β-lactoglobulin (BLG) using molecular docking and molecular dynamics simulation methods was examined. Molecular docking studies showed that quercetin and quercitrin were bounded to the internal cavity of protein, while rutin was bounded to the entrance of the cavity because of its large structural volume. It was found that there were one-, three-, and four-hydrogen bond interactions between BLG and quercetin, quercitrin, and rutin respectively. This showed that with an increase in the number of OH groups in the flavonoid structure, there was an increase in the number of hydrogen bond interactions. The binding constants for the binding of quercetin, quercitrin, and rutin to BLG were 1.2 × 10⁶, 1.9 × 10⁶, and 7.4 × 10⁴ M^?1 respectively. The results of molecular dynamics simulation showed that the root mean square deviation (RMSD) of non-liganded BLG and BLG–ligand complexes reached equilibration after 3500 ps. The study of the radius of gyration revealed that BLG and BLG–ligand complexes were stabilized around 2500 ps, and unlike the two other complexes, there was no conformational change for BLG–quercetin. Finally, analyzing the RMS fluctuations suggested that the structure of the ligand binding site remained approximately rigid during simulation.     

The Interaction of a New Schiff Base Ligand with Human Serum Albumin: Molecular Docking and Molecular Dynamics Simulation Studies

The interaction of a new heterocyclic Schiff base bearing pyridine and pyrimidine cycles, with human serum albumin (HSA) using molecular docking and molecular dynamics simulation methods was examined. Molecular docking studies showed that the ligand was bonded to the IB domain of the protein. It was found that there was one hydrogen bond interaction between HSA and the ligand. The standard Gibbs free energy for binding of the ligand to HSA was calculated as ?9.63 kcal.mol^?1. The results of the molecular dynamics simulation showed that the root mean square deviation (RMSD) of the non-liganded HSA and the HSA–ligand complex reached equilibration after 1000 ps. The study of the radius of gyration revealed that there was a conformational change when the HSA–ligand complex was formed. Finally, analyzing the RMS fluctuations (RMSF) suggested that the structure of the ligand binding site remained approximately rigid during the simulation.     

Docking accuracy enhanced by QM-derived protein charges

Effects of protein polari sation on docking accuracy were investigated using molecular docking programme AutoDock 4 in which topology-specific empirical Gasteiger charges were replaced with Polarised protein-specific charges (PPC) to represent quantum mechanics- polarised protein. Docking was successfully conducted for 50 diverse protein–ligand complexes. The docking with PPC charges shows a decrease in the root-mean-square deviation (RMSD) values of ligands compared to those from the docking with Gasteiger charges. Ligand binding orientations and their key interactions such as hydrogen bonding interactions in X-ray structures were substantially reproduced in complexes docked using PPC scheme with 98% of the RMSDs of the best docking poses less than 2 Å compared to 74% in the docking with Gasteiger charges. Considerable improvements in docking accuracy were observed by simply altering the atomic partial charges in the scoring function, which reflects the importance of protein polarisation in molecular docking. Further research can be carried out to (1) include polarisation of both ligands and proteins to account for polarisation effects within protein and between protein and ligand, and (2) develop a PPC-based scoring function to increase the docking accuracies for protein–ligand complexes from a larger variety of protein families.     

Deoxyribonucleic Acid and Bovine Serum Albumin Interaction with the Asymmetric Schiff Base Ligand and Its Molybdenum (VI) Complex: Multi Spectroscopic and Molecular Docking Studies

The interaction of an asymmetric Schiff base ligand derived from allylamine and 2,3-dihydroxybenzaldehyde and its molybdenum (VI) complex with deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) were studied using spectroscopic and molecular docking methods. The spectroscopic results revealed that the DNA and BSA affinity for binding the Mo(VI) complex is greater than its ligand. Furthermore, the molecular docking calculations showed that H-bond, hydrophobic, π-π and π-cation interactions had the dominant roles in the stability of the compound-BSA complexes. The DNA interaction results suggested that the compounds interacted with DNA by the groove binding mechanism.     

基于接触数引导的迭代多组独立分子动力学模拟实现配体-蛋白质结合与解离过程

配体的结合与解离过程在蛋白质实现其生物学功能方面非常关键,因此对这些高度动态过程的研究变得非常重要. 尽管已有实验方法可以确定蛋白质-配体复合物的三维结构,但一般仅可获得静态图片. 随着计算机算力的快速提高以及算法的优化,分子动力学模拟在探索配体的结合与解离过程方面具有诸多优势. 然而,当系统变得足够大时,分子动力学模拟的时间和空间尺度成为了巨大的挑战. 本工作提出了一种研究配体-蛋白质结合与解离的增强采样工具,它基于配体和蛋白质之间形成的接触数来引导迭代多组独立分子动力学模拟. 在腺苷酸激酶的模拟结果中,观测到配体的结合和解离过程,而使用传统分子动力学模拟在同一时间尺度下则无法实现这一过程.     

苯并咪唑/苯并噻唑类T315I突变型Abl抑制剂的结合机理和分子设计

Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T315I mutant, makes the search for new Abl T315I inhibitors a very interesting challenge in medicinal chemistry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T315I. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T315I activities were designed and presented to experimenters for reference.     

Insights into the interaction and binding mode of a set of antifungal azoles as inhibitors of potential fungal enzyme-based targets

Azole-containing compounds are a kind of chemical entities of natural and synthetic origin having a wide-range of activities. They are therefore considered as important moieties for fungicide development, mostly due to the possible action on several enzyme-based targets. As part of our research on fungicidal agents, the relationship between the ligand-enzyme affinities of several synthetic azole-containing compounds against a set of fungal enzyme-based targets was in silico evaluated through molecular docking. The affinity values of the test compounds were mostly higher than those of the respective test controls. Binding modes between enzymes and test compounds were firstly investigated through Vina scores and ligand–residue interactions. Furthermore, statistically relationships among docking scores were successfully found by multivariate analysis. They were mostly correlated with reported MIC₈₀ values, so it denoted an evident discrimination of the test compounds. Strong electron withdrawing groups on phenylacrylamide moiety were responsible for establishing stronger complexes with the enzyme targets, being trichodiene synthase and α-l-fucosidase the most important ones. Moreover, stability of a set of representative protein/ligand complexes was also analyzed by 10 ns molecular dynamics simulations (MD). Significant differences into the MD runs were detected and directly correlated to docking performances. Finally, docking affinity scores and HOMO–LUMO energy gaps resulted well predicted by comparative molecular field analysis (CoMFA) models, demonstrating the structure type is particularly associated with those calculated properties and these results were thus consistent with the respective validation parameters.     

Soyasapogenol-B as a Potential Multitarget Therapeutic Agent for Neurodegenerative Disorders: Molecular Docking and Dynamics Study

Neurodegenerative disorders involve various pathophysiological pathways, and finding a solution for these issues is still an uphill task for the scientific community. In the present study, a combination of molecular docking and dynamics approaches was applied to target different pathways leading to neurodegenerative disorders such as Alzheimer’s disease. Initially, abrineurin natural inducers were screened using physicochemical properties and toxicity assessment. Out of five screened compounds, a pentacyclic triterpenoid, i.e., Soyasapogenol B appeared to be the most promising after molecular docking and simulation analysis. Soyasapogenol B showed low TPSA (60.69), high absorption (82.6%), no Lipinski rule violation, and no toxicity. Docking interaction analysis revealed that Soyasapogenol B bound effectively to all of the targeted proteins (AChE, BuChE MAO-A, MAO-B, GSK3β, and NMDA), in contrast to other screened abrineurin natural inducers and inhibitors. Importantly, Soyasapogenol B bound to active site residues of the targeted proteins in a similar pattern to the native ligand inhibitor. Further, 100 ns molecular dynamics simulations analysis showed that Soyasapogenol B formed stable complexes against all of the targeted proteins. RMSD analysis showed that the Soyasapogenol B–protein complex exhibited average RMSD values of 1.94 Å, 2.11 Å, 5.07 Å, 2.56 Å, 3.83 Å and 4.07 Å. Furthermore, the RMSF analysis and secondary structure analysis also indicated the stability of the Soyasapogenol B–protein complexes.     

Spectroscopic and docking studies of the binding of two stereoisomeric antioxidant catechins to serum albumins

The interactions of two stereoisomeric antioxidant flavonoids, catechin (C) and epicatechin (EC) with bovine serum albumin (BSA) and human serum albumin (HSA), have been investigated by steady state and time resolved fluorescence, phosphorescence, circular dichroism (CD), FTIR and protein–ligand docking studies. The steady-state fluorescence studies indicate a single binding site for both the ligands. FTIR spectra suggest that in both the albumins, C and EC stabilize the α-helix at the cost of a corresponding loss in the β-sheet structure. CD studies have been carried out using (±)C, and both the epimers (+)C and (?)C. The low temperature phosphorescence and protein–ligand [(+), (?) and (±) forms of C and EC] docking studies indicate that the ligands bind in the proximity of Trp 134 of BSA and Trp 214 of HSA, thereby changing their solvent accessible surface areas (ASA). Asn 158 and Glu 130 side chains are found to be within the hydrogen bonding distance from the phenolic –OH groups of C and EC in the case of BSA complex. C and EC are located within the binding pocket of sub-domain IIa of HSA.     

Comparison of ligand migration and binding in heme proteins of the globin family

The binding of small diatomic ligands such as carbon monoxide or dioxygen to heme proteins is among the simplest biological processes known. Still, it has taken many decades to understand the mechanistic aspects of this process in full detail. Here, we compare ligand binding in three heme proteins of the globin family, myoglobin, a dimeric hemoglobin, and neuroglobin. The combination of structural, spectroscopic, and kinetic experiments over many years by many laboratories has revealed common properties of globins and a clear mechanistic picture of ligand binding at the molecular level. In addition to the ligand binding site at the heme iron, a primary ligand docking site exists that ensures efficient ligand binding to and release from the heme iron. Additional, secondary docking sites can greatly facilitate ligand escape after its dissociation from the heme. Although there is only indirect evidence at present, a preformed histidine gate appears to exist that allows ligand entry to and exit from the active site. The importance of these features can be assessed by studies involving modified proteins(via site-directed mutagenesis) and comparison with heme proteins not belonging to the globin family.     

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer’s disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl l Tryptophan (l-NAT) on NK1R, this is the first in silico screening of l-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The l-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The l-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of l-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein–ligand interactions with an acceptable root mean square deviation. The protein–ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein–ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of l-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.

Graphic Abstract

     

Ultrasound-assisted extraction of saffron bioactive compounds; separation of crocins,picrocrocin, and safranal optimized by artificial bee colony

In this work, a four-factor five-level full factorial central composite design (CCD) was used to optimize the ultrasound-assisted extraction (UAE) of saffron major components, namely picrocrocin, safranal and crocin. The process parameters included ethanol concentration (0–100%), extraction time (2–10 min), duty cycle (0.2–1.0) and ultrasonic amplitude (20–100%). The extracted compounds were measured both by spectrophotometry and chromatography techniques. The results revealed that the middle concentrations of ethanol and relatively long process durations along with high duty cycles and ultrasonic amplitudes had the most profound impact on the yields of the extracted bioactives. UAE was optimized using response surface methodology (RSM) and artificial bee colony (ABC); a comparison between these methods indicated their optimization power was approximately the same. According to the RSM analysis, an ethanol concentration of 58.58%, extraction time of 6.85 min, duty cycle of 0.82 and amplitude of 91.11% were the optimum extraction conditions, while the optimal conditions resulting from ABC were 53.07%, 7.32 min, 0.93 and 100% for the UAE variables respectively. Finally, HPLC analysis was carried out on the UAE optimum extract resulting from RSM. Four crocetin esters were detected in the optimal extract.     

Ligand diffusion in proteins via enhanced sampling in molecular dynamics

Computational simulations in biophysics describe the dynamics and functions of biological macromolecules at the atomic level. Among motions particularly important for life are the transport processes in heterogeneous media. The process of ligand diffusion inside proteins is an example of a complex rare event that can be modeled using molecular dynamics simulations. The study of physical interactions between a ligand and its biological target is of paramount importance for the design of novel drugs and enzymes. Unfortunately, the process of ligand diffusion is difficult to study experimentally. The need for identifying the ligand egress pathways and understanding how ligands migrate through protein tunnels has spurred the development of several methodological approaches to this problem. The complex topology of protein channels and the transient nature of the ligand passage pose difficulties in the modeling of the ligand entry/escape pathways by canonical molecular dynamics simulations. In this review, we report a methodology involving a reconstruction of the ligand diffusion reaction coordinates and the free-energy profiles along these reaction coordinates using enhanced sampling of conformational space. We illustrate the above methods on several ligand–protein systems, including cytochromes and G-protein-coupled receptors. The methods are general and may be adopted to other transport processes in living matter.     

Molecular interaction of silybin with hyaluronidase: A spectroscopic and molecular docking study

In this study, the molecular interaction of silybin with hyaluronidase was investigated by spectroscopic methods and molecular docking. It was found that silybin had strong ability to quench the intrinsic fluorescence of hyaluronidase by a static quenching procedure. The binding constants were obtained at three temperatures (293, 298, and 310 K). The results of synchronous fluorescence and three-dimensional fluorescence and molecular docking showed that silybin bound into the hyaluronidase cavity site and the binding of silybin to hyaluronidase could induce micro-environmental and conformational changes in hyaluronidase, which resulted in the reduced hyaluronidase activity. The thermodynamic parameter analysis and molecular docking experiments revealed that all types of non-covalent interaction, including hydrogen bonding interaction, van der Waals forces, hydrophobic interaction, and electrostatic interaction were present in the binding process of silybin with hyaluronidase. The results obtained here will provide direct evidence at a molecular level to understand the mechanism of the inhibitory effect of silybin against hyaluronidase.     

Interaction mechanism between copolymer inhibitor and β-dicalcium silicate surface based on molecular dynamics simulation

Copolymer inhibitor with multifunctional groups has a good effect on inhibiting the secondary reaction in the clinker leaching process for alumina production, but the inhibition mechanism of the copolymer is not clear yet. In this paper, molecular dynamics simulation was used to study the adsorption process of the copolymer inhibitor with multifunctional groups, such as acrylic acid-vinyl alcohol copolymer (PAV) and acrylic acid-hydroxypropyl acrylate copolymer (PAH), on the β-dicalcium silicate (C₂S) crystal surface, and reveal its inhibiting mechanism. Meanwhile, the polyacrylic acid (PAA) with only the carboxyl group also is simulated for comparing the inhibition effect with copolymer inhibitors. The results show that the binding energy between copolymer (PAV, PAH) and β-C₂S is greater than that of PAA with a single functional group. The order of binding energy is as follows: PAH?>?PAV?>?PAA. In aqueous solution, the water molecule can restrict the degree of deformation of polymers, increase the distance between polymers and β-C₂S and then lead to weakening of the adsorption of polymers on the crystal surface. The comprehensive and coordination effect of carboxyl and hydroxyl functional groups in PAV and PAH can strengthen the adsorption of copolymers on the β-C₂S surface. The different spatial distribution of multifunctional groups in the molecular structure has a different influence on the adsorption of the copolymer. The results can provide a theoretical basis for researching new and highly effective copolymer inhibitors with multifunctional groups.

Compared the adsorption state: The comprehensive and coordinate action of carboxyl and hydroxyl groups of the inhibitor with multifunctional groups make the inhibitor have a stronger adsorption ability on the surface of β-C₂S than that with a single functional group. The results obtained in this paper can provide a theoretical basis for the research and development of new and highly effective polymeric inhibitors with multifunctional groups.

Highlights

The interaction between copolymer and β-C₂S was investigated by MD simulation.

The binding energy order between polymers and β-C₂S is PAH?>?PAV?>?PAA.

The presence of water molecules can weaken the adsorption of the copolymer on the surface of β-C₂S.

The comprehensive and coordinate action of carboxyl and hydroxyl groups of the inhibitor with multifunctional groups make the inhibitor have a stronger adsorption ability on the surface of β-C₂S than that with a single functional group.     

Processes of DNA condensation induced by multivalent cations： Approximate annealing experiments and molecular dynamics simulations

The condensation of DNA induced by spermine is studied by atomic force microscopy （AFM） and molecular dynamics （MD） simulation in this paper. In our experiments, an equivalent amount of multivalent cations is added to the DNA solutions in different numbers of steps, and we find that the process of DNA condensation strongly depends on the speed of adding cations. That is, the slower the spermine cations are added, the slower the DNA aggregates. The MD and steered molecular dynamics （SMD） simulation results agree well with the experimental results, and the simulation data also show that the more steps of adding multivalent cations there are, the more compact the condensed DNA structure will be. This investigation can help us to control DNA condensation and understand the complicated structures of DNA--cation complexes.     

分子对接和荧光光谱法研究槲皮素与β-葡萄糖苷酶的相互作用

结合分子对接法和光谱法,研究了槲皮素与β-葡萄糖苷酶的相互作用及作用机理。首先利用AutoDock 4.2软件对β-葡萄糖苷酶与槲皮素、竞争性抑制剂对硝基苯-β-D-巯基葡萄糖的分子对接分别进行研究,然后采用荧光光谱法研究了槲皮素与β-葡萄糖苷酶的结合反应,并测定了结合常数。结果表明：这种相互作用使β-葡萄糖苷酶发生内源荧光猝灭,属于静态猝灭机制。通过计算得到槲皮素与β-葡萄糖苷酶在17,27和37 ℃下结合常数分别为4.36×104,4.04×104和3.18×104 L·mol-1。氢键和疏水作用对槲皮素与β-葡萄糖苷酶的结合起重要作用,也存在静电作用力。分子对接研究和荧光光谱实验两者相互补充,可从理论和实验两方面协同研究槲皮素与β-葡萄糖苷酶之间的相互作用。     

Molecular dynamics simulation of oxygen diffusion in dry and water-containing brown coal

Moisture content of brown coal has a pronounced impact on O₂ diffusion during coal oxidation. The transport behaviour of O₂ in dry and hydrated brown coal matrix with 10, 20, and 30?wt% moisture contents have been studied by molecular dynamics (MD) simulations at 298.15?K and 0.1?MPa. By analysing the diffusion characteristics of O₂, it is found that the diffusion process results from jumps of O₂ molecules between adjacent cavities in the coal matrix. With the increase of moisture content, the swelling extent of coal matrix increases in the range of 10–30?wt%, resulting in increased cavity volume, cavity interconnectivity, and mobility of coal macromolecule. These factors are all beneficial to the transport process of O₂ molecule. In addition, O₂ molecule prefers to reside in the available water-poor coal cavity and unoccupied region of water-rich cavity according to the estimated binding energies.