Combining ligand-based and structure-based drug design approaches to study the structure-activity relationships of a β-carboline derivative series

In this study, we investigated the structure-activity relationships of a series of β-carboline alkaloid derivatives using the 2D-QSAR and molecular docking, in order to identify the mode of interaction between β-carboline derivatives and the PLK1 kinase, and determine their key substituents responsible for the cytotoxic activity. The obtained QSAR models using multiple linear regression (MLR) and partial least squares (PLS) methods showed a high correlation between the experimental activity and the predicted one by PLS (R²_PLS?=?0.82, q²?=?0.72) and MLR (R²_MLR?=?0.82, q²?=?0.72). An external dataset was used to test the extrapolation power of the models which resulted in an R²_PLS (EV)?=?0.76; RMSE?=?0.39. The 2D-QSAR analysis reveals that lipophilicity plays an important role in the cytotoxic activity of this group of β-carboline derivatives. Indeed, the molecular docking study into the active site of the polo-like kinase (PLK1) revealed that the most active ligand 57 shows higher binding energy and interacts, especially by H-bonds and hydrophobic interactions, with the active site of the PLK1 kinase. Consequently, the results obtained from the 2D-QSAR and docking studies provided a useful tool to design new and potent β-carboline derivatives as cytotoxic agents.     

Mechanism for binding to the flexible cavity of permethylatedα-cyclodextrin

The cavity of -cyclodextrin (-CDx) is too small to includeo-toluic acid (o-TA) while it is filled byp-toluic acid (p-TA) to form a relatively stable inclusion complex. Such strict selectivity is ascribed to a rigid structure of the -CDx cavity which is stabilized by intramolecular hydrogen bonds between the O(2) hydroxyl groups and the O(3) hydroxyl groups of adjacent glucopyranose units. Meanwhile, the substrate selectivity of hexakis (2,3,6-tri-O-methyl)--CDx (TMe--CDx) remains somewhat obscure because of the flexible nature of its cavity. The absence of the intramolecular hydrogen bonds seems to cause the flexible nature of the TMe--CDx cavity leading to an induced-fit type inclusion. The structures of the inclusion complexes have been presented on the basis of the¹H NMR data. The thermodynamic parameters indicate that the complexation of TMe--CDx witho-TA orp-TA is the entropically favorable process. The entropically favorable complexation of TA with TMe--CDx seems to occur through dehydration from the CO₂H group of TA which is situated at the hydrophobic CDx cavity. The dipole-dipole interaction has been regarded as the force which dominates the orientation of the polar guest molecule in the CDx cavity.     

Inhibitor screening of pharmacological chaperones for lysosomal β-glucocerebrosidase by capillary electrophoresis

Pharmacological chaperones (PCs) represent a promising therapeutic strategy for treatment of lysosomal storage disorders based on enhanced stabilization and trafficking of mutant protein upon orthosteric and/or allosteric binding. Herein, we introduce a simple yet reliable enzyme assay using capillary electrophoresis (CE) for inhibitor screening of PCs that target the lysosomal enzyme, β-glucocerebrosidase (GCase). The rate of GCase-catalyzed hydrolysis of the synthetic substrate, 4-methylumbelliferyl-β-d-glucopyranoside was performed using different classes of PCs by CE with UV detection under standardized conditions. The pH and surfactant dependence of inhibitor binding on recombinant GCase activity was also examined. Enzyme inhibition studies were investigated for five putative PCs including isofagomine (IFG), ambroxol, bromhexine, diltiazem, and fluphenazine. IFG was confirmed as a potent competitive inhibitor of recombinant GCase with half-maximal inhibitory concentration (IC ₅₀ ) of 47.5 ± 0.1 and 4.6 ± 1.4 nM at pH 5.2 and pH 7.2, respectively. In contrast, the four other non-carbohydrate amines were demonstrated to function as mixed-type inhibitors with high micromolar activity at neutral pH relative to acidic pH conditions reflective of the lysosome. CE offers a convenient platform for characterization of PCs as a way to accelerate the clinical translation of previously approved drugs for oral treatment of rare genetic disorders, such as Gaucher disease.     

Exploring the binding mechanism of thioflavin-T to the β-amyloid peptide by blind docking method

Using blind dock method,we find that thioflavin-T(ThT) can bind to both monomers and fibrils of the full-length β-amyloid peptide(Aβ1-42) and has a higher binding affinity to the fibrils.It is shown that the hydrophobic interaction between the ligand(ThT) and substrate(Aβ1-42) are stronger than hydrogen bonds.Furthermore,ThT tends to be located near the C-terminus of Aβ monomer through hydrophobic and electrostatic interactions,while it tends to contact the residues Met35 and Gly27 of the fibril surface mainly through hydrophobic interaction.Finally,according to the docking results and ThT fluorescence assay,a kinetic equation is proposed to deduce the aggregation rate coefficient of Aβ1-42.     

Quantitative structure-activity relationship of compounds binding to estrogen receptor β based on heuristic method

Estrogen compounds may pose a serious threat to the health of humans and wildlife.The estrogen receptor (ER) exists as two subtypes,ERβ and ERβ.Compounds might have different relative affinities and binding modes for ERβ and ERβ.In this study,the heuristic method was performed on 31 compounds binding to ERβ to select 5 variances most related to the activity (LogRBA) from 1524 variances,which were then employed to develop the best model with the significant correlation and the best predictive power (r2 = 0.8...     

Computational study on the encapsulation of ethylparaben into β-cyclodextrin

Two models namely A and B were considered to investigate the inclusion process of ethylparaben into β-CD cavity by means PM3, HF/6-31G (d) and B3LYP/6-31G (d). The obtained results with PM3 method clearly indicate that the formed complexes are energetically favored with or without solvent; the B complex is found more favored than A complex. The calculated deformations energies show that the geometry of β-CD is deformed in the complexation process on the other hand the ethylparaben do not undergo deformation. Finally, From NBO analysis, the donor and acceptor interactions between ethylparaben and β-CD were analyzed and discussed.     

Overview of the SAMPL6 host–guest binding affinity prediction challenge

Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host–guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host–guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host–guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host–guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host–guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.     

Computational insights about the dynamic behavior for the inclusion process of deprotonated and neutral aspirin in β-cyclodextrin

A high-efficiency microwave irradiation (MW) assisted protocol was proposed to synthesize series SPE-β-CD with specific degree of substitution (DS) in the sodium hydroxide solution. This protocol provided an eco-friendly way to modify the cyclodextrins with bulky sulfopropyl substituent on the purpose of avoiding organic solvents and high quantities of thermal energy. Temperature and energy distribution became more uniform under the new method accordingly. Therefore, not only the reaction time reduced significantly from over 20 h to a few hours, but also the DS increased up according to ¹H NMR spectroscopy, MS and elemental analysis results. Most importantly, the effects of reaction parameters on DS were compared both under MW method and conventional heating method, and were sufficiently studied to guarantee the aforementioned results could be better reproduced and DS of products could become more specific through the synthesis process. Products structures were characterized by FT-IR, DSC, and ¹³C NMR spectroscopy.     

Theoretical studies on the binding energy of β-sheet models

In this paper, B3LYP and MP2 methods are used to investigate the binding energy of seventeen antiparallel and parallel β-sheet models. The results indicate that the binding energy obtained from B3LYP calculations is weaker than that obtained from MP2 calculations but the relative binding energy yielded by B3LYP is almost the same as that by MP2. For the antiparallel β-sheets in which two N-H⋯O=C hydrogen bonds can form either a large hydrogen-bonded ring or a small hydrogen-bonded ring, the binding energy increases obviously when one large ring unit is added, whereas it only changes slightly when one small ring unit is added because of the secondary electrostatic repulsive interaction existing in the small ring unit which is estimated to be about 20 kJ/mol. For the parallel β-sheet models, the binding energy increases almost exactly linearly with the increase of the chain length.     

Quantitative structure-activity relationship analysis of β-amyloid aggregation inhibitors

Inhibiting the aggregation process of the β-amyloid peptide is a promising strategy in treating Alzheimer’s disease. In this work, we have collected a dataset of 80 small molecules with known inhibition levels and utilized them to develop two comprehensive quantitative structure–activity relationship models: a Bayesian model and a decision tree model. These models have exhibited high predictive accuracy: 87% of the training and test sets using the Bayesian model and 89 and 93% of the training and test sets, respectively, by the decision tree model. Subsequently these models were used to predict the activities of several new potential β-amyloid aggregation inhibitors and these predictions were indeed validated by in vitro experiments. Key chemical features correlated with the inhibition ability were identified. These include the electro-topological state of carbonyl groups, AlogP and the number of hydrogen bond donor groups. The results demonstrate the feasibility of the developed models as tools for rapid screening, which could help in the design of novel potential drug candidates for Alzheimer’s disease.     

Hydroxylated oxanes as xyloside analogs for determination of the minimal binding requirements of β4GalT7

β-1,4-Galactosyltransferase 7 (β4GalT7) is a key enzyme in the biosynthesis of glycosaminoglycan (GAG) chains. Natural and synthetic xylosides can be used to both inhibit and prime GAG synthesis by acting as inhibitors or substrates for β4GalT7. In this report, we exploit hydroxylated oxanes as deoxygenated xyloside analogs to clarify the minimum protein-ligand interactions required for galactosylation and/or inhibition. Enantiomerically pure substances were synthesized using a chiral pool approach whereas the corresponding racemates were obtained from simple starting materials. The results of a β4GalT7 assay show that a single hydroxyl group on an oxane ring is insufficient to induce galactosylation or inhibition, which implies that at least two substituents, one of which being 3-OH, needs to be present.     

Semiempirical prediction of the hyperpolarizabilities for cyanovinyl-substituted donor-acceptor molecules

We present here a systematically theoretical study on the nonlinearities and their structure-property relationship of cyanovinyl-substituted donor-acceptor molecules by virtue of semiem-pirical PM3/AM1-FF approach.Good consistency between measured and calculated hyperpolarizabil-ities is obtained.Results show that conformation has a significant effect on hyperpolarizabilities.The torsion angle change between two conjugated parts of the molecular systems can substantially alter the nonlinearities.The total amount of charge transfer difference from donor to acceptor has been introduced to understand the microscopic nature of the nonlinear optical properties for the title molecules.General guidelines may be sought out in the search of molecules with large values of β Some molecules with large molecular hyperpolarizabilities can be predicted by the optimization for the longer π-electron systems with both acceptor and donor groups.     

A sequence-based computational model for the prediction of the solvent accessible surface area for α-helix and β-barrel transmembrane residues

Predicting the solvent accessible surface area (ASA) of transmembrane (TM) residues is of great importance for experimental researchers to elucidate diverse physiological processes. TM residues fall into two major structural classes (α-helix membrane protein and β-barrel membrane protein). The reported solvent ASA prediction models were developed for these two types of TM residues respectively. However, this prevents the general use of these methods because one cannot determine which model is suitable for a given TM residue without information of its type. To conquer this limitation, we developed a new computational model that can be used for predicting the ASA of both TM α-helix and β-barrel residues. The model was developed from 78 α-helix membrane protein chains and 24 β-barrel membrane protein. Its prediction ability was evaluated by cross validation method and its prediction result on an independent test set of 20 membrane protein chains. The results show that our model performs well for both types of TM residues and outperforms other prediction model which was developed for the specific type of TM residues. The prediction results also proved that the random forest model incorporating conservation score is an effective sequence-based computational approach for predicting the solvent ASA of TM residues.     

Evolution of the international workshops on quantitative structure-activity relationships (QSARs) in environmental toxicology†

This presentation will review the evolution of the workshops from a scientific and personal perspective. From their modest beginning in 1983, the workshops have developed into larger international meetings, regularly held every two years. Their initial focus on the aquatic sphere soon expanded to include properties and effects on atmospheric and terrestrial species, including man. Concurrent with this broadening of their scientific scope, the workshops have become an important forum for the early dissemination of all aspects of qualitative and quantitative structure-activity research in ecotoxicology and human health effects. Over the last few decades, the field of quantitative structure/activity relationships (QSARs) has quickly emerged as a major scientific method in understanding the properties and effects of chemicals on the environment and human health. From substances that only affect cell membranes to those that bind strongly to a specific enzyme, QSARs provides insight into the biological effects and chemical and physical properties of substances. QSARs are useful for delineating the quantitative changes in biological effects resulting from minor but systematic variations of the structure of a compound with a specific mode of action. In addition, more holistic approaches are being devised that result in our ability to predict the effects of structurally unrelated compounds with (potentially) different modes of action. Research in QSAR environmental toxicology has led to many improvements in the manufacturing, use, and disposal of chemicals. Furthermore, it has led to national policies and international agreements, from use restrictions or outright bans of compounds, such as polychlorinated biphenyls (PCBs), mirex, and highly chlorinated pesticides (e.g. DDT, dieldrin) for the protection of avian predators, to alternatives for ozone-depleting compounds, to better waste treatment systems, to more powerful and specific acting drugs. Most of the recent advances in drug development could not have been achieved without the use of QSARs in one form or another. The pace of such developments is rapid and QSARs are the keystone to that progress. These workshops have contributed to this progress and will continue to do so in the future.     

A functional feature analysis on diverse protein–protein interactions: application for the prediction of binding affinity

Protein–protein interactions (PPIs) play crucial roles in diverse cellular processes. There are different types of PPIs based on the composition, affinity and whether the association is permanent or transient. Analyzing the diversity of PPIs at the atomic level is crucial for uncovering the key features governing the interactions involved in PPI. A systematic physico-chemical and conformational studies were implemented on interfaces involved in different PPIs, including crystal packing, weak transient heterodimers, weak transient homodimers, strong transient heterodimers and homodimers. The comparative analysis shows that the interfaces tend to be larger, less planar, and more tightly packed with the increase of the interaction strength. Meanwhile the strong interactions undergo greater conformational changes than the weak ones involving main chains as well as side chains. Finally, using 18 features derived from our analysis, we developed a support vector regression model to predict the binding affinity with a promising result, which further demonstrate the reliability of our studies. We believe this study will provide great help in more thorough understanding the mechanism of diverse PPIs.     

Simultaneous prediction of binding free energy and specificity for PDZ domain–peptide interactions

Interactions between protein domains and linear peptides underlie many biological processes. Among these interactions, the recognition of C-terminal peptides by PDZ domains is one of the most ubiquitous. In this work, we present a mathematical model for PDZ domain–peptide interactions capable of predicting both affinity and specificity of binding based on X-ray crystal structures and comparative modeling with Rosetta. We developed our mathematical model using a large phage display dataset describing binding specificity for a wild type PDZ domain and 91 single mutants, as well as binding affinity data for a wild type PDZ domain binding to 28 different peptides. Structural refinement was carried out through several Rosetta protocols, the most accurate of which included flexible peptide docking and several iterations of side chain repacking and backbone minimization. Our findings emphasize the importance of backbone flexibility and the energetic contributions of side chain-side chain hydrogen bonds in accurately predicting interactions. We also determined that predicting PDZ domain–peptide interactions became increasingly challenging as the length of the peptide increased in the N-terminal direction. In the training dataset, predicted binding energies correlated with those derived through calorimetry and specificity switches introduced through single mutations at interface positions were recapitulated. In independent tests, our best performing protocol was capable of predicting dissociation constants well within one order of magnitude of the experimental values and specificity profiles at the level of accuracy of previous studies. To our knowledge, this approach represents the first integrated protocol for predicting both affinity and specificity for PDZ domain–peptide interactions.     

Polymeric adsorbents with peptide pendants as artificial receptors for β-Mactam antibiotics by mimicking the binding sites of β-lactamases

A scries of polymeric adsorbents with peptide pendants were designed as the artificial receptors of β-laetarn antibiotics by mimicking the structures of binding site in β-lactamases.Crosslinked poly(N,N-dimethyl acry-lamide) gel as a carrier was prepared by suspension copolyrnerization of N,N-dimethyl acrylamide and N,N-bisacryl-diaminoethane and then functionalized with ethylenediamine after partial hydrolysis.Using solid-phase peptide synthesis with symmetrical anhydride of protected amino acid step by step,various peptide pendants were respectively anchored onto the functionalized carrier.The adsorption properties of these peptide-containing adsorbents for β-lactam antibiotics such as ampicillin and cefotaxime were then studied.The results showed that only those adsorbents in which peptide chains contained more than one lysine residues could obviously adsorb both β-lactams and that static interaction as well as hydrogen bond played an important role during the adsorption