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Abstract: For years, conventional drug design at G-protein coupled receptors (GPCRs) has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The recent discovery of more and more physiologically relevant GPCR dimers/oligomers suggests that selectively targeting these complexes or designing small molecules that inhibit receptor–receptor interactions might provide new opportunities for novel drug discovery. To uncover the fundamental mechanisms and dynamics governing GPCR dimerization/oligomerization, it is crucial to understand the dynamic process of receptor–receptor association, and to identify regions that are suitable for selective drug binding. This minireview highlights current progress in the development of increasingly accurate dynamic molecular models of GPCR oligomers based on structural, biochemical, and biophysical information that has recently appeared in the literature. In view of this new information, there has never been a more exciting time for computational research into GPCRs than at present. Information-driven modern molecular models of GPCR complexes are expected to efficiently guide the rational design of GPCR oligomer-specific drugs, possibly allowing researchers to reach for the high-hanging fruits in GPCR drug discovery, i.e. more potent and selective drugs for efficient therapeutic interventions. [Copyright &y& Elsevier]

Abstract: Zinc is an essential element for nutrition as well as for the proper development and function of brain cells, and its traces are present in a wide range of foods. It is a constituent of many enzyme systems and is an integral part of insulin and of the active site of intracellular enzymes. However, excessive accumulation of zinc or its release from the binding sites may become detrimental for neurons. With the aim to better understand the molecular mechanisms of the interaction of zinc ions with cell membranes, it was incubated with intact human erythrocytes, isolated unsealed human erythrocyte membranes (IUM), cholinergic murine neuroblastoma cells, and molecular models of cell membranes. These consisted in bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes present in the outer and inner monolayers of most plasmatic cell membranes, particularly that of human erythrocytes, respectively. The capacity of zinc ions to perturb the bilayer structures of DMPC and DMPE was assessed by X-ray diffraction, DMPC large unilamellar vesicles (LUV) and IUM were studied by fluorescence spectroscopy, intact human erythrocytes were observed with scanning electron microscopy (SEM), and neuroblastoma cell morphology was observed under inverted microscope. This study presents evidence that 0.1mM Zn and higher concentrations affect cell membrane and molecular models. [Copyright &y& Elsevier]

When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level. We searched for possible binding sites of Srx using a binding site prediction method and uncovered two possible inhibition mechanisms of Srx by J14. Using molecular dynamics simulations and binding free energy calculations, we confirmed that J14 binds to the ATP binding site; therefore, J14 acts as a competitive inhibitor of ATP, settling the question of the two mechanisms. Based on the inhibition mechanism revealed at the atomic level, we designed several derivatives of J14, which led to LMT-328 (4-(((4-(4-(2-Chlorophenyl)piperazin-1-yl)-6-(2,4-dihydroxy-5-isopropylphenyl)pyrimidin-2-yl)thio)methyl)benzoic acid), which is possibly an even more potent inhibitor than J14. Image 1 • Inhibition of sulfiredoxin (Srx) induces ROS-mediated cancer cell death. • Two possible inhibition mechanisms by Srx inhibitor J14 were uncovered. • J14 binds to the ATP binding site and acts as a competitive inhibitor of ATP. • New potent inhibitor LMT-328 was designed based on the revealed inhibition mechanism. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of phenyltriazolyl derivatives were developed as Type I1/2 ALK inhibitors. • 12k exhibited promising inhibitory effects on ALKWT (3.7 nM) and ALKL1196M (6.8 nM). • 12k induced apoptosis and inhibited colony formation & tumor migration on H2228 cells. • 12k formed key interactions in ATP binding site and hydrophobic back pocket of ALK. Based on the high-throughput screening hit BY-1 , a series of phenyltriazolyl derivatives were developed. Satisfyingly, most compounds were detected moderate to excellent antitumor effects against Karpas299 and H2228 cells. Among them, 12k bearing 4‑hydroxypiperidinyl group exhibited the optimal activities against tested cells with IC 50 values of 51 nM and 175 nM, as well as promising inhibitory effects on ALKWT (3.7 nM) and ALKL1196M (6.8 nM). Unlike the conventional type-I ALK inhibitors, molecular models identified 12k as an allosteric type-I1/2 inhibitor by forming key interactions in both the ATP binding region and the hydrophobic back pocket of ALK. Intriguingly, 12k could dose-dependently induce apoptosis on H2228 cell and inhibit colony formation and tumor cell migration. Taken together, the rationalization of 12k may shed new light on the identification of novel allosteric type-I1/2 ALK inhibitors. [ABSTRACT FROM AUTHOR]

The binding mechanism of aripiprazole (APZ) with human serum albumin (HSA) in the absence and presence of three cyclodextrins (CyDs) (β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and (2,6-di- O -methyl)-β-cyclodextrin) was studied by fluorescence, ultraviolet–visible absorption, nuclear magnetic resonance, and circular dichroism (CD) spectroscopy. The CD results revealed some degree of recovery of refolding caused by APZ after the addition of CyD. The Stern–Volmer quenching constant and binding constant of the APZ–HSA interaction were smaller in the presence of the three CyDs. The ultraviolet–visible absorption results indicated that APZ formed 1:1 complex with the three CyDs. The 1 H NMR spectra of CyD showed chemical shift and resolution loss of proton after the addition of HSA. Molecular modeling studies showed that both APZ and CyD bind to HSA. The process was initiated through inclusion of free APZ molecules by CyD and the increase in steric hindrance of CyD–HSA binding. [ABSTRACT FROM AUTHOR]

Highlights: [•] Homology model of human protein arginine methyltransferase 1 was built. [•] MD simulation and ASP were used to consider receptor flexibility. [•] Cavity around ASP84 was proposed as a potential binding site. [•] The predominant binding poses of known ligands were proposed. [ABSTRACT FROM AUTHOR]

Highlights: [•] This work is focusing on deciphering the site-selective binding of jatrorrhizine to HSA. [•] The spectroscopic methods and molecular modeling have been chosen as the study tools. [•] The binding mechanisms, and a series of bind parameters have been explored. [ABSTRACT FROM AUTHOR]

Abstract: A series of thiazolone derivatives was designed and synthesized as potential HCV NS5B allosteric polymerase inhibitors at the allosteric site thumb II. Their antiviral activity was evaluated and molecular modeling was utilized to give further envision on their probable binding modes in the allosteric binding site. Among the tested molecules, compound 9b displayed sub-micromolar inhibitory activity with an EC50 of 0.79 μM indicating excellent potency profile. It also showed good safety profile (CC50 ≥ 75 μM and SI ≥ 94.3). [Copyright &y& Elsevier]

Abstract: 2A protease of the pathogenic coxsackievirus B3 is key to the pathogenesis of inflammatory myocarditis and, therefore, an attractive drug target. However lack of a crystal structure impedes design of inhibitors. Here we predict 3D structure of CVB3 2Apro based on sequence comparison and homology modeling with human rhinovirus 2Apro. The two enzymes are remarkably similar in their core regions. However they have different conformations at the N-terminal. A large number of N-terminal hydrophobic residues reduce the thermal stability of CVB3 2Apro, as we confirmed by fluorescence, western blot and turbidity measurement. Molecular dynamic simulation revealed that elevated temperature induces protein motion that results in frequent movement of the N-terminal coil. This may therefore induce successive active site changes and thus play an important role in destabilization of CVB3 2Apro structure. [Copyright &y& Elsevier]

Abstract: 4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA–topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex–Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA–topo I complex in order to clarify the topo I activity of 7h. [Copyright &y& Elsevier]

Abstract: A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC50 values of 14±9 and 13±9μM, respectively. Additionally, compound 15a showed the highest potency (IC50 =10±6μM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores. [Copyright &y& Elsevier]

Abstract: We describe a very coarse-grained molecular model for the simulation of myosin V on an actin filament. The molecular representation is hierarchical with the finest level representing secondary structure elements (end-points) which are grouped into domains which are then grouped into molecules. Each level moves with a Brownian-like motion both in translation and rotation. Molecular integrity is maintained by steric exclusion and inter-domain restraints. A molecular description is developed for a myosin dimer on a actin filament with binding interactions also specified between domains to simulate both loose and tight binding. The stability of the model was tested in the pre- and post-power-stroke conformations with simulations in both states being used to test the preferred binding site of the myosin on the filament. The effects of the myosin twofold symmetry and the restriction of an attached cargo were also tested. These results provide the basis for the development of a dynamic model of processive motion. [Copyright &y& Elsevier]

Abstract: A series of novel cinnamic acid metronidazole ester derivatives have been designed and synthesized, and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Compound 3h showed the most potent biological activity (IC50 =0.62μM for EGFR and IC50 =2.15μM for HER-2). Docking simulation was performed to position compound 3h into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against MCF-7. Compound 3h with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent. [Copyright &y& Elsevier]

Abstract: The interaction between lomefloxacin (LMF) and human lactoferrin (Hlf) was studied by using fluorescence, circular dichroism (CD) spectroscopic and molecular modeling measurements. By the fluorescence quenching results, it was found that the binding constant K A=8.69×105 Lmol−1, and number of binding sites n=1.75 at physiological condition. Experimental results observed showed that the binding of LMF to Hlf induced conformational changes of Hlf. The participation of tyrosyl and tryptophanyl residues of protein was also estimated in the drug–Hlf complex by synchronous fluorescence. The quantitative analysis data of far-UV CD spectra from that of the α-helix 37.4% in free Hlf to 30.2% in the LMF–Hlf complex further confirmed that secondary structure of the protein was changed by LMF. Near-UV CD showed perturbations around tryptophan and tyrosine residues which involves perturbations of tertiary structure. The thermodynamic parameters like, ΔH° and ΔS°, have been calculated to be 63.411kJmol−1 and 231.104Jmol−1 K−1, respectively. Thermodynamic analysis showed that hydrophobic interactions were the main force in the binding site but the hydrogen bonding and electrostatic interaction could not be excluded which in agreement with the result of molecular docking study. The distance r between donor and acceptor was obtained according to fluorescence resonance energy transfer (FRET) and found to be 1.78nm. The interaction between LMF and Hlf has been verified as consistent with the static quenching procedure and the quenching mechanism is related to the energy transfer. Furthermore, the study of molecular modeling that LMF could bind to the α-helixes between Pro145–Asn152 and Phe167–Gln172 regions and hydrophobic interaction was the major acting force for the binding site, which was in agreement with the thermodynamic analysis. [Copyright &y& Elsevier]

Abstract: l-Arabinitol 4-dehydrogenase (LAD1; EC 1.1.1.12) is an enzyme in the l-arabinose catabolic pathway of fungi that catalyzes the conversion of l-arabinitol into l-xylulose. The primary objective of this work is to identify the catalytic and coenzyme binding domains of LAD1 from Hypocrea jecorina in order to provide better insight into the possible catalytic events in these domains. The 3D structure of NAD+-dependent LAD1 was developed based on the crystal structure of human sorbitol dehydrogenase as a template. A series of molecular mechanics and dynamics operations were performed to find the most stable binding interaction for the enzyme and its ligands. Using the verified model, a docking study was performed with the substrate l-arabinitol, Zn2+ and NAD+. This study found a catalytic Zn2+ binding domain (Cys66, His91, Glu92 and Glu176) and a cofactor NAD+ binding domain (Gly202, ILeu204, Gly205, Cys273, Arg229 and Val298) with strong hydrogen bonding contacts with the substrate and cofactor. The binding pockets of the enzyme for l-arabinitol, NAD+, and Zn2+ have been explicitly defined. The results from this study should guide future mutagenesis studies and provide useful clues for engineering enzymes to improve the utilization of polyols for rare sugar production. [Copyright &y& Elsevier]

Abstract: Molecular dynamics (MD) simulations of four-stranded G-quadruplex DNA complexes formed by the sequence d(TTAGGG)4 and the TQMP ligand are presented. The TQMP complex was examined both in two possible binding modes (diagonal loop and parallel loop positions). Simulations show that the G-quadruplex DNAs with two K+ ions in the central channel are fairly stable during 30 ns MD runs in explicit water box. π–π stacking and ion effect were studied with DFT calculations on the minimized MD average structure. From trajectories of MD runs, the interaction of TQMP with G-quadruplex DNA is indeed shown to correspond to the two different binding modes. Free energy analysis showed that in gas phase, the interaction between TQMP and G-quadruplex DNA is mainly electrostatic. But in water medium, the TQMP ligand preferentially binds in the diagonal loop position, the selectivity being due to a complex balance between apolar and polar contributions to the complexation free energy. [Copyright &y& Elsevier]

Abstract: A series of mono- and di-substituted N-arylaminomethylene malonates have been used to probe the potential of utilizing additional H-bonding contacts in the ubiquinone binding channel, for selective inhibition between either human or Plasmodium DHODH. Altered ‘head’ group functionalities have been utilized in order to probe the role of specific functionalities within the inhibitors in terms of enzyme affinity and selectivity. [Copyright &y& Elsevier]

Abstract: A series of pyrazolo[1,5-α]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme. [Copyright &y& Elsevier]

Abstract: A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP. [Copyright &y& Elsevier]

Abstract: The effect of hypericin photoactivation on mitochondria of human prostate carcinoma cells was studied using a range of mitochondrial inhibitors. Oligomycin significantly enhanced hypericin phototoxicity while atractyloside and antymicin A conferred a significant protection. Use of myxothiazol did not affect cell survival following hypericin photoactivation. These results signify a protective role for F1F0-ATP synthase running in reverse mode, and a significant photodamage at the quinone-reducing site of mitochondrial complex III. In light of these results, we performed molecular modeling of hypericin binding to complex III. This revealed three binding sites, two of which coincided with the quinol-oxidizing and quinone-reducing centers. Using submitochondrial particles we examined hypericin as a possible substrate of complex III and compared this to its natural substrate, ubiquinone-10. Our results demonstrate uniquely that hypericin is an efficient substrate for complex III, and this activity is inhibited by myxothiazol and antimycin A. We further demonstrated that hypericin photosensitization completely inactivated complex III with ubiquinone as substrate. The ability to enhance HYP potency by inhibition of F1F0-ATP synthase or depress HYP efficacy by inhibition at the Qi site of complex III provides a potential to increase the therapeutic index of HYP and amplify its PDT action in tumor cells. [Copyright &y& Elsevier]

Abstract: The ATP-binding cassette (ABC) transporter multidrug resistance protein 5 (MRP5) contributes to the cellular export of organic anions, including guanosine 3′–5′ cyclic monophosphate (cGMP). The structural knowledge of this protein is limited, and in lack of an MRP5 X-ray structure, a model of MRP5 was constructed based on the homology with the bacterial ABC transporter Sav1866 from Staphylococcus aureus, which has been crystallised in an outward-facing, substrate releasing conformation. Two putative binding sites were identified, and docking of cGMP indicated that TMHs 1–3, 6, 11 and 12 were in contact with the ligands in binding site 1, while TMHs 1, 3, 5–8 were in contact with the ligands in binding site 2. The proposed MRP5 model may be used for further experimental studies of the molecular structure and function of this member of the ABC-transporter superfamily. [Copyright &y& Elsevier]

Cites the formation of a human melanocortin 4 receptor molecular model. Introduction of His residues into the receptor protein to form metal ion binding sites; Insertion of micromolar affinity binding sites for zinc between transmembrane regions where the metal ion can activate the peptide; Impact of the activation on the binding of the G-protein coupled receptor; Prediction of the helicase orientation.

Reactive Red195 (RR195) was the first synthetic color patented for textile dying in 1856. Azo dyes have arisen considerable environmental concerns in recent decades due to the large volume of water they require throughout the coloring process and the polluted of industrial sewage. Azo dye due to their chemical composition, including aromatic rings, azoic linkages, and amino groups, are not bio-degradable and exceedingly resistant in the aquatic environment, posing an acute threat to human health. In this investigation, to estimate the toxicity of the RR195 at the protein level, the influences of RR195 on human serum albumin (HSA) were described by molecular modeling, steady-state fluorescence, ultraviolet-visible spectroscopy (UV–Vis), circular dichroism spectroscopy (CD), and Thermal stability (Tm). The alteration in entropy (∆S) and enthalpy (∆H) showed that hydrophobic forces were the dominant intermolecular forces in the binding of the RR195 to HSA. The binding constant of HSA–RR195 is high, presenting that RR195, which has a high affinity to HSA. The changes of protein secondary structure in the presence of the RR195 approved by CD spectroscopy method. A small reduction in the RG value of the HSA-RR195 system demonstrated a conformational difference in the compaction of HSA. • The Binding constant for Reactive red 195 - Human Serum Albumin is high. • The Effect of Reactive red 195 on Human Serum Albumin structure is reported for the first time. • The interaction of Reactive red 195 to Human Serum Albumin is spontaneous. [ABSTRACT FROM AUTHOR]

• A 3D homology model of hTRPV4 was built and the binding pocket between hTRPV4 and its antagonist was predicted for the first time. • Two 9-(4-piperidinyl)-purine derivatives were designed, synthesized and investigated for hTRPV4 inhibitory activity. Compound B2 was discovered as a novel hTRPV4 antagonist. • The result provided suitable guidance for discovering and developing antagonists of TRPV4. The transient receptor potential vanilloid type 4 (TRPV4) is a polymodal receptor. Antagonists of human TRPV4 (hTRPV4) represent a novel therapeutic approach for acute lung injury (ALI). However, the discovery of various hTRPV4 antagonists has been difficult due to the unavailability of 3D-structure of hTRPV4 protein. We constructed the 3D-structure of hTRPV4 protein by homology modelling, and the binding pocket of antagonist with hTRPV4 was predicted for the first time. The pocket was consistent with the same subfamily rabbit TRPV5. The detailed interactions of different protein-ligand complexes were calculated by molecular docking and molecular dynamics (MD) simulation, and the outcome revealed the rationality of the binding pocket. Based on the docking and MD results of this model and the structure of compound A2, a TRPV4 antagonist reported in literature, two small molecular compounds, B1 and B2, were designed and synthesized as hTRPV4 antagonists. The results of biological evaluation in vitro showed that these compounds have good inhibitory activity on hTRPV4. Moreover, the results were in good agreement with those predicted by molecular simulation, which in turn suggested that the modeling 3D structure and the predicted active sites of hTRPV4 are reasonable and reliable. The compound B2, with novel structure and potent inhibitory activity against hTRPV4, can be a promising lead compound for discovering new hTRPV4 antagonists in the future. [ABSTRACT FROM AUTHOR]

The vital enzyme O-linked β-N-acetylglucosamine transferase (OGT) catalyzes the O-GlcNAcylation of intracellular proteins coupling the metabolic status to cellular signaling and transcription pathways. Aberrant levels of O-GlcNAc and OGT have been linked to metabolic diseases as cancer and diabetes. Here, a new series of peptidomimetic OGT inhibitors was identified highlighting the compound LQMed 330, which presented better IC 50 compared to the most potent inhibitors found in the literature. Molecular modeling study of selected inhibitors into the OGT binding site provided insight into the behavior by which these compounds interact with the enzyme. The results obtained in this study provided new perspectives on the design and synthesis of highly specific OGT inhibitors. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Biologically important hydrazide-hydrazone (–(C=O)NHN=CH) functionality was located at two different positions on 4,6-dimethoxyindole moiety and novel compounds 11a-c and 12a-c were generated by the condensation reactions of indole hydrazones 7 and 8 , derived from the corresponding indole carbaldehydes 4 and 6 , and carboxylic acids 9a-c in the presence of amide coupling reagent (EDC). The anticholinesterase potency was investigated towards the acetyl- and butrylcholinesterase enzymes (AChE and BChE) and complementary determination of biological potency was obtained by the evaluation of binding scores. The compound 11b resulted the best binding behaviors due to the hydrophobic interactions with the responsible amino acids on the different active sites of enzymes pocket. The structural analysis revealed that the most favorable binding pose was mainly dependent on the presence of aromatic moiety administered by the benzoic acid as well as the hydrazide-hydrazone linker but not related with the location on indole ring. Most importantly, the biological study was found to be compatible with the molecular modeling study and the highest inhibition was determined in the presence of compound 11b with the values of 83.31 and 73.55 for AChE and BChE, respectively. • The concise and high yielded synthesis of novel hydrazide-hydrazone derivatives located on different positions on 4,6-dimethoxyindole systems are achieved by the amide coupling reactions. • The presence of indole heterocyclic ring with the hydrazide-hydrazone moiety create new potent anticholinesterase inhibitors. • Molecular docking studies reveal the structural insights of novel hydrazide-hydrazones by the interactions on the anticholinesterase enzymes. [ABSTRACT FROM AUTHOR]

We recently reported the discovery of a novel protein stabilizing dipeptide, glycyl-D-asparagine, through a structure-based approach. As the starting hypothesis leading to the discovery, we postulated a stabilizing effect achieved by binding of the dipeptide to an aggregation prone region on the protein's surface. Here we present a detailed study of the interaction mechanism between the dipeptide and Interferon-alpha-2A (IFN) through the construction of a Markov state model from molecular dynamics trajectories. We identify multiple binding sites and compare these to aggregation prone regions. Additionally, we calculate the lifetime of the protein-excipient complex. If the excipient remained bound to IFN after administration, it could alter the protein's therapeutic efficacy. We establish that the lifetime of the complex between IFN and glycyl-D-asparagine is extremely short. Under these circumstances, stabilization by stoichiometric binding is consequently no impediment for a safe use of an excipient. [ABSTRACT FROM AUTHOR]

• The first time to explain selectivity from the perspective of the difference between Nav1.7-VSD4 and Nav1.4-VSD4 key amino acids. • Com1 and Com2 were selected to prove hypothesis and ideas combining molecular docking, MD simulations and Binding free energy calculations. • The causes of different conformations in key amino acids Tyr1386 and Tyr1537 were analyzed. • The difference of selectivity between Com1 and Com2 was explained from the structural point of view. Here, we focused on exploring the selectivity mechanism against Nav1.7 over Nav1.4 due to different binding modes of two selected inhibitors. By the superposition of Nav1.7 and Nav1.4 proteins, we selected the most homologous chain of Nav1.7 with Nav1.4, defining the active site of Nav1.4-VSD4 based on the aryl sulfonamide binding site of Nav1.7-VSD4. Comparison of the conformations exhibited by Tyr1386 (Nav1.4) and Tyr1537 (Nav1.7) suggested that the steric hindrance caused by Tyr1386 owned primary influence on inhibition selectivity, which was further verified through molecular docking and MD simulation of two representative inhibitors. Our finding would be helpful for discovery of selective Nav1.7 inhibitors over Nav1.4. [ABSTRACT FROM AUTHOR]

CIA17 is a PP2-like, homodimeric lectin made up of 17 kDa subunits present in the phloem exudate of ivy gourd (Coccinia indica). Isothermal titration calorimetric (ITC) studies on the interaction of chitooligosaccharides [(GlcNAc) 2–6 ] showed that the dimeric protein has two sugar binding sites which recognize chitotriose with ~70-fold higher affinity than chitobiose, indicating that the binding site is extended in nature. ITC, atomic force microscopic and non-denaturing gel electrophoresis studies revealed that the high-affinity interaction of CIA17 with chitohexaose (K a = 1.8 × 107 M−1) promotes the formation of protein oligomers. Computational studies involving homology modeling, molecular docking and molecular dynamics simulations on the binding of chitooligosaccharides to CIA17 showed that the protein binding pocket accommodates up to three GlcNAc residues. Interestingly, docking studies with chitohexaose indicated that its two triose units could interact with binding sites on two protein molecules to yield dimeric complexes of the type CIA17-(GlcNAc) 6 -CIA17, which can extend in length by the binding of additional chitohexaose and CIA17 molecules. These results suggest that PP2 proteins play a role in plant defense against insect/pathogen attack by directly binding with the higher chain length chitooligosaccharides and forming extended, filamentous structures, which facilitate wound sealing. Unlabelled Image • CIA17 is a PP2 family phloem exudate lectin which recognizes chitooligosaccharides • ITC studies show that CIA17 exhibits 70-fold higher affinity for chitotriose than chitobiose • ITC and AFM studies show that CIA17-chitohexaose interaction leads to the formation of protein oligomers • Modeling studies showed that two triose units of chitohexaose simultaneously interact with two CIA17 molecules • Interaction of CIA17 and longer chitooligosaccharides yields filamentous structures, which facilitate wound sealing [ABSTRACT FROM AUTHOR]

Abstract: Gamma aminobutyric acid type A (GABA-A) receptors are an important therapeutic target in insomnia treatment. The GABA-A protein structure is still not available. In this study, a reliable structure of GABA-A receptor was built and validated by several criteria. Zolpidem was predicted to gain the highest binding affinity at the BZ-binding site and be surrounded by α1-His129, α1-Tyr187, α1-Gly228, α1-Thr234, α1-Tyr237, γ2-Met96, γ2-Phe116, and γ2-Met169. In addition, GABA formed five hydrogen bonds with α1-Arg159, β2-Glu179, and β2-Tyr181 and was surrounded by the residues α1-Phe92, α1-Arg147, β2-Tyr181, β2-Thr184, β2-Thr226, and β2-Tyr229 at the GABA-binding site. The two simulation results were consistent with the experimental assay, which suggested that the simulated GABA-A receptor was reliable. Jujuboside A, which was considered the effective suanzaoren constituent, had difficulty penetrating the blood–brain barrier. Besides, jujuboside A was unable to bind at both binding sites due to its large structural volume. However, jujubogenin that was hydrolyzed from jujuboside A showed the most compatible binding pose and formed five hydrogen bonds with the key residues, β2-Thr226 and β2-Tyr229, at the GABA-binding site. In addition, according to a docking study, jujubogenin gained higher scoring values, which indicated a higher binding affinity. Moreover, the adsorption, distribution, metabolism, excretion, and toxicity (ADMET) descriptors predicted that jujubogenin had high blood–brain barrier penetration. Conclusively, jujubogenin was suggested to be the effective suanzaoren constituent for exerting the sedative function via GABA-A receptor. [Copyright &y& Elsevier]

Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer’s disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC 50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent Aβ N3pE−40 -lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and h ERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer’s agents. [ABSTRACT FROM AUTHOR]

Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition ( K i s >10,000 nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. [ABSTRACT FROM AUTHOR]

A series of substituted pyrazolines ( 2a – e , 3a – h and 6a – c ) and isoxazolines ( 4a – e ) were synthesized and their structures were established on the basis of IR, 1 H NMR, 13 C NMR and mass spectra. All the synthesized compounds were tested against two bacterial and four fungal strains and found to exhibit moderate to potent antifungal activity. Compounds 2b , 4c , 4d and 6a–c exhibited significant activity against all tested fungal strains. MIC values of all the active compounds were comparable with standard drug fluconazole. The results of the in silico molecular docking study supported the antifungal activity of the synthesized compounds. [ABSTRACT FROM AUTHOR]

Abstract: In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results. [Copyright &y& Elsevier]

Abstract: Searching for new anti-inflammatory agents, we have prepared a series of potential COX-2 inhibitors, 1-(4,6-dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-Δ2-pyrazolines (3) and 1-(4,6-dimethylpyrimidin-2-yl)-3-trifluoromethylpyrazoles (4), by refluxing 2-hydrazino-4,6-dimethylpyrimidine (1) with a number of trifluoromethyl-β-diketones (2) in ethanol. Further dehydration of compounds (3) to the corresponding 1-(4,6-dimethylpyrimidin-2-yl)-5-trifluoromethylpyrazoles (5) was also achieved. Fifteen of these compounds were screened for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay. While all the compounds exhibited significant anti-inflammatory activity (47–76%) as compared to indomethacin (78%), 3-trifluoromethylpyrazoles (4) were found to be the most effective agents (62–76%). To rationalize this anti-inflammatory activity, docking experiments molecular dynamics simulations were performed to study the ability of these compounds to bind into the active site of the COX-2 enzyme. [Copyright &y& Elsevier]

Abstract: A series of 7,8-dehydrorutaecarpine derivatives were synthesized and characterized as potential multifunctional agents for treatment of Alzheimer's disease (AD). All of these synthetic compounds showed high acetylcholinesterase (AChE) inhibitory activity with IC50 values ranged from 0.60 to 196.7 nM, and good selectivity for AChE over butyrylcholinesterase (BuChE) (125- to 3225-fold). A Lineweaver–Burk plot and molecular modeling study indicated these compounds could bind to both catalytic active site and the peripheral anionic site of AChE. Besides, compounds showed higher activity of inhibiting AChE-induced amyloid-beta (Aβ) aggregation than curcumin, higher anti-oxidative activity than Trolox, and could also be good metal chelators. Considering their low cytotoxicity, our results indicated that these derivatives provide good templates for developing new multifunctional agents for AD treatment. [Copyright &y& Elsevier]

Abstract: Stereoselectivity of reversible inhibition of butyrylcholinesterase (BChE; EC 3.1.1.8) by optically pure ethopropazine [10-(2-diethylaminopropyl)phenothiazine hydrochloride] enantiomers and racemate was studied with acetylthiocholine (0.002–250 mM) as substrate. Molecular modelling resulted in the reaction between BChE and ethopropazine starting with the binding of ethopropazine to the enzyme peripheral anionic site. In the next step ethopropazine ‘slides down’ the enzyme gorge, resulting in interaction of the three rings of ethopropazine through π–π interactions with W82 in BChE. Inhibition mechanism was interpreted according to three kinetic models: A, B and C. The models differ in the type and number of enzyme–substrate, enzyme–inhibitor and enzyme–substrate–inhibitor complexes, i.e., presence of the Michaelis complex and/or acetylated BChE. Although, all three models reproduced well the BChE activity in absence of ethopropazine, model A was poor in describing inhibition with ethopropazine, while models B and C were better, especially for substrate concentrations above 0.2 mM. However model C was singled out because it approaches fulfilment of the one step-one event criteria, and confirms the inhibition mechanism derived from molecular modelling. Model C resulted in dissociation constants for the complex between BChE and ethopropazine: 61, 140 and 88 nM for R-enantiomer, S-enantiomer and racemate, respectively. The respective dissociation constants for the complexes between acetylated BChE and ethopropazine were 268, 730 and 365 nM. Butyrylcholinesterase had higher affinity for R-ethopropazine. [Copyright &y& Elsevier]

Abstract: We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; (2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔG bind-cald for both noscapine and Br-noscapine (3.915 and 3.025kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔG bind-Expt of 3.570 and 2.988kcal/mol, derived from K d values); and (3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin. [Copyright &y& Elsevier]

Abstract: Novel non-nucleobase-derived inhibitors of the angiogenic enzyme, thymidine phosphorylase, have been identified using molecular modelling, synthesis and biological evaluation. These inhibitors are 2,4,5-trioxoimidazolidines bearing N-(substituted)phenylalkyl groups, together with, in most cases, N′-(CH2)n-carboxylic acid, ester or amide side chains. The best compound from this series is 3-(2,4,5-trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide, with an IC50 of 40 μM against Escherichia coli TP. Molecular modelling suggests that this ligand, when complexed with closed-cleft human TP, would have the phenylalkyl group in the active site region normally occupied by a thymine-containing structure. [Copyright &y& Elsevier]

Abstract: In this study, homology modeling, molecular docking and molecular dynamics simulation were performed to explore structural features and binding mechanism of some inhibitors of chemokine receptor type 5 (CCR5), and to construct a model for designing new CCR5 inhibitors for preventing HIV attachment to the host cell. A homology modeling procedure was employed to construct a 3D model of CCR5. For this procedure, the X-ray crystal structure of bovine rhodopsin (1F88A) at 2.80Å resolution was used as template. After inserting the constructed model into a hydrated lipid bilayer, a 20ns molecular dynamics (MD) simulation was performed on the whole system. After reaching the equilibrium, twenty-four CCR5 inhibitors were docked in the active site of the obtained model. The binding models of the investigated antagonists indicate the mechanism of binding of the studied compounds to the CCR5 obviously. Moreover, 3D pictures of inhibitor–protein complex provided precious data regarding the binding orientation of each antagonist into the active site of this protein. One additional 20ns MD simulation was performed on the initial structure of the CCR5–ligand 21 complex, resulted from the previous docking calculations, embedded in a hydrated POPE bilayer to explore the effects of the presence of lipid bilayer in the vicinity of CCR5–ligand complex. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes [Copyright &y& Elsevier]

Abstract: A series of N-substituted-3-[(2′-hydroxy-4′-prenyloxy)-phenyl]-5-phenyl-4,5-dihydro-(1H)-pyrazolines were synthesized and tested on human monoamine oxidase-A and -B isoforms. Structure–activity relationships and molecular modelling showed that some substitutions, such as benzyloxy or chlorine atom, improve the best interaction with active site of hMAO-B. [ABSTRACT FROM AUTHOR]

Abstract: The interaction between syringin and HSA has been studied by AFM, molecule modeling, fluorescence, UV–vis, FTIR and CD spectroscopy. Fluorescence results revealed that syringin can enhance the intensity of HSA fluorescence. The enhancement data was analyzed by the equation which developed by Bhattacharya et al. The results showed that there was one primary syringin binding site on HSA with a binding constant of 2.97×104 M−1 at 295K. Thermodynamic analysis by Van Hoff equation found enthalpy change (ΔH 0) and entropy change (ΔS 0) were −5.23kJmol−1 and 103.34Jmol−1 K−1 respectively, which indicated the hydrophobic interaction was the predominant force in the binding process. Competitive experiments showed a displacement of warfarin by syringin, which indicated that the binding site was located at the drug site I. AFM results revealed that the dimension of the individual HSA molecules was larger after interaction with syringin. The secondary structure compositions of free HSA and HSA–syringin complex were estimated by FTIR and CD spectra. [ABSTRACT FROM AUTHOR]

Abstract: Ligand-based active site alignment is a widely adopted technique for the structural analysis of protein–ligand complexes. However, existing tools for ligand alignment treat the ligands as rigid objects even though most biological ligands are flexible. We present LigAlign, an automated system for flexible ligand alignment and analysis. When performing rigid alignments, LigAlign produces results consistent with manually annotated structural motifs. In performing flexible alignments, LigAlign automatically produces biochemically reasonable ligand fragmentations and subsequently identifies conserved structural motifs that are not detected by rigid alignment. [ABSTRACT FROM AUTHOR]

Protein Ser/Thr phosphatase-1 (PP1) catalyzes the majority of eukaryotic protein dephosphorylation reactions in a highly regulated and selective manner. Recent studies have identified an unusually diversified PP1 interactome with the properties of a regulatory toolkit. PP1-interacting proteins (PIPs) function as targeting subunits, substrates and/or inhibitors. As targeting subunits, PIPs contribute to substrate selection by bringing PP1 into the vicinity of specific substrates and by modulating substrate specificity via additional substrate docking sites or blocking substrate-binding channels. Many of the nearly 200 established mammalian PIPs are predicted to be intrinsically disordered, a property that facilitates their binding to a large surface area of PP1 via multiple docking motifs. These novel insights offer perspectives for the therapeutic targeting of PP1 by interfering with the binding of PIPs or substrates. [ABSTRACT FROM AUTHOR]

Abstract: By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule. [Copyright &y& Elsevier]

Abstract: Chagas’ disease (CD) has been responsible for many deaths and disabilities mainly in South America. Currently, 40 million people are at risk of acquiring this disease and, existing therapies are still unsatisfactory, presenting harsh side effects. Therefore, the development of new chemical entities to reverse this state is critical. A series of peptidomimetics, developed by Mc Kie et al. (2001) , showed a reversible and competitive inhibition against Trypanosoma cruzi Trypanothione Reductase (TR). These inhibitors may be used as basis of lead compounds in the design of new drug candidates for the treatment of CD. In this work, we have docked this series of peptidomimetics into the TR binding site, using the FlexX algorithm as implemented in the Sybyl program, in order to access the binding mode of this class of compounds in the target enzyme. [Copyright &y& Elsevier]

Abstract: A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed. [Copyright &y& Elsevier]

Abstract: The antimalarial acitivity of hydroxyethylamines, synthesized from the reaction of intermediated hydroxyethypiperazines with benzenesulfonyl chlorides or benzoyl chlorides, has been evaluated in vitro against a W2 Plasmodium falciparum clone. Some of the nineteen tested derivatives showed a significant activity in vitro, thus turning into a promising new class of antimalarials. In addition, a molecular modeling study of the most active derivative (5l) was performed and its most probable binding modes within plasmepsin II enzyme were identified. [Copyright &y& Elsevier]

Abstract: Immunoassay for low molecular weight food contaminants, such as pesticides, veterinary drugs, and mycotoxins is now a well-established technique which meets the demand for a rapid, reliable, and cost-effective analytical method. However, due to limited understanding of the molecular structure of antibody binding sites and antigenic epitopes, as well as the intermolecular binding forces that come into play, the traditional ‘trial and error’ method used to develop antibodies still remains the method of choice. Therefore, development of enhanced immunochemical techniques for specific- and generic-assays, requires new approaches for antibody design that will improve affinity and specificity of the antibody in a more rapid and economic manner. Computer-assisted molecular modeling (CAMM) has been demonstrated to be a useful tool to help the immunochemist develop immunoassays. CAMM methods can be used to help direct improvements to important antibody features, and can provide insights into the effects of molecular structure on biological activity that are difficult or impossible to obtain in any other way. In this review, we briefly summarize applications of CAMM in immunoassay development, including assisting in hapten design, explaining cross-reactivity, modeling antibody–antigen interactions, and providing insights into the effects of the mouse body temperature on the three-dimensional conformation of a hapten during antibody production. The fundamentals and theory, programs and software, limitations, and prospects of CAMM in immunoassay development were also discussed. [Copyright &y& Elsevier]

Abstract: 3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H37Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values. [Copyright &y& Elsevier]