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Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor for mainly treating non-small cell lung cancer (NSCLC). This investigation focused on to clarify in detail the binding behavior between human α-1 acid glycoprotein (HAG) and ceritinib by means of multi-spectroscopic and molecular modeling approaches. Fluorescence data obtained at four different temperatures indicated ceritinib quenched the endogenous fluorescence of HAG by a static quenching mechanism. Based on the K b value at 10 5  M -1 level, it can be inferred that the binding affinity between both is strong. From findings of thermodynamic parameter analysis, the competitive experiments with ANS and sucrose as well as molecular dynamic (MD) simulation, it can be inferred that hydrophobicity, hydrogen bonding, van der Waals forces as well as electrostatic interactions exist in the binding interaction between ceritinib and HAG. The findings from UV absorption, circular dichroism, and synchronous fluorescence spectroscopy indicated that the change in the microenvironment around the protein structure, secondary structure and tryptophan residues occurred after interaction with ceritinib. The data from FRET analysis confirmed that the non-radiative energy transfer between the two existed and the binding distance between the acceptor (ceritinib) and donor (HAG) was 2.11 nm. Meantime, the influence of Ca 2+ , Cu 2+ , Ni 2+ , Co 2+ , and Zn 2+ ions on the binding interaction of ceritinib with HAG were obvious, especially Zn 2+ ion., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Asbtract Filamentous temperature-sensitive protein Z (FtsZ), playing a key role in bacterial cell division, is regarded as a promising target for the design of antimicrobial agent. This study is looking for potential high-efficiency FtsZ inhibitors. Ligand-based pharmacophore and E-pharmacophore, virtual screening and molecular docking were used to detect promising FtsZ inhibitors, and molecular dynamics simulation was used to study the stability of protein-ligand complexes in this paper. Sixty-three inhibitors from published literatures with pIC 50 ranging from 2.483 to 5.678 were collected to develop ligand-based pharmacophore model. 4DXD bound with 9PC was selected to develop the E-pharmacophore model. The pharmacophore models validated by test set method and decoy set were employed for virtual screening to exclude inactive compounds against ZINC database. After molecular docking, ADME analysis, IFD docking and MM-GBSA, 8 hits were identified as potent FtsZ inhibitors. A 50 ns molecular dynamics simulation was implemented on the compounds to assess the stability between potent inhibitors and FtsZ. The results indicated that the candidate compounds had a high docking score and were strongly combined with FtsZ by forming hydrogen bonding interactions with key amino acid residues, and van der Waals forces and hydrophobic interactions had significant contribution to the stability of the binding. Molecular dynamics simulation results showed that the protein-ligand compounds performed well in both the stability and flexibility of the simulation process.

Nanoparticles (NPs) are one of the interesting and widely studying issues mainly because of their particular physico-chemical features and broad applications in the field of biomedical sciences, such as diagnosis and drug delivery. In this study, the interaction of iron nanoparticles (Fe-NPs) with Tau protein and PC12 cell, as potential nervous system models, was investigated with a range of techniques including dynamic light scattering, intrinsic fluorescence spectroscopy, circular dichroism, [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium-bromid] assay, and acridine orange/ethidium bromide (AO/EB) dual staining method. An inverse correlation between Stern and Volmer constant (K SV ) and temperature indicated a probable static quenching mechanism occurred between Tau protein and Fe-NPs. The number of binding site (n = 0.86) showed that there is almost one binding site of Fe-NP per protein. The negative values of ∆H (-53.21 kJ/mol) and T∆S (-42.44 kJ/mol) revealed that Fe-NPs interacts with Tau protein with dominate role of hydrogen bonds and van der Waals interactions and this interaction was spontaneous (∆G = -10.77 kJ/mol). Also, Fe-NPs stabilized the random coil structure of Tau protein. Moreover, Fe-NPs reduced PC12 cells viability by fragmentation of DNA in an apoptotic manner. In conclusion, induced conformational changes of Tau protein and cytotoxicity of PC12 cells by Fe-NP were revealed to be in a concentration and time-dependent manner.

With the growing number of labor-intensive data in the pharmaceutical industries and public domain for protein-ligand complexes, a significant challenge is still remaining in managing and leveraging this vast information. Here, a standalone application is presented for analysis, organization, and illustration of structural data and molecular interactions for exploiting 3D-structures into simple 1D fingerprints. The utility of the approach was shown in unraveling a feasible solution for post-processing of docking results in parallel with providing fruitful analysis for users in order to investigate molecular interactions. Remarkably, all interaction possibilities including (hydrogen bond, water-bridged, electrostatic, and hydrophobic as well as π- π and cation-π interactions) are supported both in the form of fingerprints and compelling reports. These investigations are mainly considered based on right orientation, location, and geometry of the interacting pairs rather than the acquisition of the energy terms. The reasonable efficiency of our application in different models was comparable to recent methods It is clearly presented that FLIP provides a faster way to generate usable fingerprints for ligand and protein binding modes. FLIP is free for academic use and is available at: http://zistrayan.com/development/download/flip/package.zip., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Intracellular aggregation of proteins is thought to be involved in the aetiology of various neurodegenerative diseases. In particular, mutations in the SOD1 gene are linked to the familial form of amyotrophic lateral sclerosis (ALS). Recently, we developed a regression model for estimating the survival time of ALS patients carrying mutations in SOD1. This model was built based on an analysis of the stability of hydrogen bonds formed in SOD1 mutant proteins during a molecular dynamics (MD) simulation. In the present paper, the regression model was improved by taking into account a new hydrogen-bond property that reflects the conservation measure of a hydrogen bond in the space of protein conformational states. Conformational conservation of hydrogen bonds, being obtained with elastic network (EN) models, allowed us to find eight hydrogen bonds that might affect the pathogenic SOD1 mutants' properties in addition to the bonds that were found via MD in our previous work. The correlation coefficient between survival time of patients with ALS-linked mutations in SOD1 predicted within the improved model and that observed in the literature was 0.91. SOD1 amino acid residues forming these pathogenic hydrogen bonds are found in zinc-binding and electrostatic loops as well as at zinc-binding sites and are in contact with SOD1 aggregates, which implies that these regions are sensitive to perturbations from pathogenic mutations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this research, molecular docking and 3D-QSAR studies were carried out on a series of 79 thiazoloquin(az)olin(on)es as CD38 inhibitors. Based on docking results, four interactions including hydrogen bonding with main chain of GLU-226 (H-M-GLU-226), Van der Waals interactions with side chain of TRP-125 (V-S-TRP-125), TRP-189 (V-S-TRP-189), and THR-221 (V-S-THR-221) were considered as pharmacological interactions. Active conformation of each ligand was extracted from docking studies and was used for carrying out 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) was performed on CD38 inhibitory activities of these compounds on human and mouse. We developed CoMFA models with five components as optimum models for both data-sets. For human data-set, a model with high predictive power was developed. R 2 , RMSE, and F-test values for training set of this model were .94, .24, and 179.58, respectively, and R 2 and RMSE for its test set were .92 and .32, respectively. The q 2 and RMSE values for leave-one-out cross validation test on training set were .78 and .46, respectively, that demonstrate created model is robust. Based on extracted steric and electrostatic contour maps for this model, three inhibitors with pIC 50 larger than 8.85 were designed.

Homodimeric photosynthetic reaction centers (RCs) in green sulfur bacteria and heliobacteria are functional homologs of Photosystem (PS) I in oxygenic phototrophs. They show unique features in their electron transfer reactions; however, detailed structural information has not been available so far. We mutated PscA-Leu688 and PscA-Val689 to cysteine residues in the green sulfur bacterium Chlorobaculum tepidum; these residues were predicted to interact with the special pair P840, based on sequence comparison with PS I. Spectroelectrochemical measurements showed that the L688C and V689C mutations altered a near-infrared difference spectrum upon P840 oxidation, as well as the redox potential of P840. Light-induced Fourier transform infrared difference measurements showed that the L688C mutation induced a differential signal of the S-H stretching vibration in the P840(+)/P840 spectrum, as reported in P800(+)/P800 difference spectrum in a heliobacterial RC. Spectral changes in the 13(1)-keto C=O region, caused by both mutations, revealed corresponding changes in the electronic structure of P840 and in the hydrogen-bonding interaction at the 13(1)-keto C=O group. These results suggest that there is a common spatial configuration around the special pair sites among type 1 RCs. The data also provided evidence that P840 has a symmetric electronic structure, as expected from a homodimeric RC.

Although it is widely known that trimethylamine N-oxide (TMAO), an osmolyte used by nature, stabilizes the folded state of proteins, the underlying mechanism of action is not entirely understood. To gain further insight into this important biological phenomenon, we use the C≡N stretching vibration of an unnatural amino acid, p-cyano-phenylalanine, to directly probe how TMAO affects the hydration and conformational dynamics of a model peptide and a small protein. By assessing how the lineshape and spectral diffusion properties of this vibration change with cosolvent conditions, we are able to show that TMAO achieves its protein-stabilizing ability through the combination of (at least) two mechanisms: (i) It decreases the hydrogen bonding ability of water and hence the stability of the unfolded state, and (ii) it acts as a molecular crowder, as suggested by a recent computational study, that can increase the stability of the folded state via the excluded volume effect.