Representation of molecular structure using quantum topology with inductive logic programming in structure–activity relationships

The requirement of aligning each individual molecule in a data set severely limits the type of molecules which can be analysed with traditional structure activity relationship (SAR) methods. A method which solves this problem by using relations between objects is inductive logic programming (ILP). Another advantage of this methodology is its ability to include background knowledge as 1st-order logic. However, previous molecular ILP representations have not been effective in describing the electronic structure of molecules. We present a more unified and comprehensive representation based on Richard Bader's quantum topological atoms in molecules (AIM) theory where critical points in the electron density are connected through a network. AIM theory provides a wealth of chemical information about individual atoms and their bond connections enabling a more flexible and chemically relevant representation. To obtain even more relevant rules with higher coverage, we apply manual postprocessing and interpretation of ILP rules. We have tested the usefulness of the new representation in SAR modelling on classifying compounds of low/high mutagenicity and on a set of factor Xa inhibitors of high and low affinity.     

DFT‐based QSAR study and molecular design of AHMA derivatives as potent anticancer agents

A quantitative structure–activity relationship (QSAR) of 3‐(9‐acridinylamino)‐5‐hydroxymethylaniline (AHMA) derivatives and their alkylcarbamates as potent anticancer agents has been studied using density functional theory (DFT), molecular mechanics (MM+), and statistical methods. In the best established QSAR equation, the energy (E_NL) of the next lowest unoccupied molecular orbital (NLUMO) and the net charges (Q_FR) of the first atom of the substituent R, as well as the steric parameter (MR₂) of subsituent R₂ are the main independent factors contributing to the anticancer activity of the compounds. A new scheme determining outliers by “leave‐one‐out” (LOO) cross‐validation coefficient (q) was suggested and successfully used. The fitting correlation coefficient (R²) and the “LOO” cross‐validation coefficient (q²) values for the training set of 25 compounds are 0.881 and 0.829, respectively. The predicted activities of 5 compounds in the test set using this QSAR model are in good agreement with their experimental values, indicating that this model has excellent predictive ability. Based on the established QSAR equation, 10 new compounds with rather high anticancer activity much greater than that of 34 compounds have been designed and await experimental verification. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Assessment and acceleration of binding energy calculations for protein–ligand complexes by the fragment molecular orbital method

In the field of drug discovery, it is important to accurately predict the binding affinities between target proteins and drug applicant molecules. Many of the computational methods available for evaluating binding affinities have adopted molecular mechanics‐based force fields, although they cannot fully describe protein–ligand interactions. A noteworthy computational method in development involves large‐scale electronic structure calculations. Fragment molecular orbital (FMO) method, which is one of such large‐scale calculation techniques, is applied in this study for calculating the binding energies between proteins and ligands. By testing the effects of specific FMO calculation conditions (including fragmentation size, basis sets, electron correlation, exchange‐correlation functionals, and solvation effects) on the binding energies of the FK506‐binding protein and 10 ligand complex molecule, we have found that the standard FMO calculation condition, FMO2‐MP2/6‐31G(d), is suitable for evaluating the protein–ligand interactions. The correlation coefficient between the binding energies calculated with this FMO calculation condition and experimental values is determined to be R = 0.77. Based on these results, we also propose a practical scheme for predicting binding affinities by combining the FMO method with the quantitative structure–activity relationship (QSAR) model. The results of this combined method can be directly compared with experimental binding affinities. The FMO and QSAR combined scheme shows a higher correlation with experimental data (R = 0.91). Furthermore, we propose an acceleration scheme for the binding energy calculations using a multilayer FMO method focusing on the protein–ligand interaction distance. Our acceleration scheme, which uses FMO2‐HF/STO‐3G:MP2/6‐31G(d) at R_int = 7.0 Å, reduces computational costs, while maintaining accuracy in the evaluation of binding energy. © 2015 Wiley Periodicals, Inc.     

Natural Compounds against Neurodegenerative Diseases: Molecular Characterization of the Interaction of Catechins from Green Tea with Aβ1–42, PrP106–126, and Ataxin‐3 Oligomers

By combining NMR spectroscopy, transmission electron microscopy, and circular dichroism we have identified the structural determinants involved in the interaction of green tea catechins with Aβ1–42, PrP106–126, and ataxin‐3 oligomers. The data allow the elucidation of their mechanism of action, showing that the flavan‐3‐ol unit of catechins is essential for interaction. At the same time, the gallate moiety, when present, seems to increase the affinity for the target proteins. These results provide important information for the rational design of new compounds with anti‐amyloidogenic activity and/or molecular tools for the specific targeting of amyloid aggregates in vivo.     

Structure–activity relationship of N‐heterocyclic carbene–Pd(II)–imidazole complexes in Suzuki–Miyaura coupling between 4‐methoxyphenyl chloride and phenylboronic acid

A series of N‐heterocyclic carbene–PdCl₂–imidazole [NHC–Pd(II)–Im] complexes were synthesized and the structure of most of them was unambiguously determined by X‐ray single‐crystal diffraction. The structure–activity relationship of these complexes was investigated for the Suzuki–Miyaura coupling between 4‐methoxyphenyl chloride and phenylboronic acid, and the effect of the NHCs and Im moieties were fully discussed. The sterically hindered IPr‐based complex showed the highest catalytic activity. Copyright © 2013 John Wiley & Sons, Ltd.     

Binding conformations,QSAR, and molecular design of Alkene‐3‐quinolinecarbonitriles as Src inhibitors

A theoretical study on binding orientations and quantitative structure–activity relationship (QSAR) of a novel series of alkene‐3‐quinolinecarbonitriles acting as Src inhibitors has been carried out by using the docking study and three‐dimensional QSAR (3D‐QSAR) analyses. The appropriate binding orientations and conformations of these compounds interacting with Src kinase were revealed by the docking studies, and the established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high R² values and q² values: comparative molecular field analysis (CoMFA) model (q² = 0.748, R² = 0.972), comparative molecular similarity indices analysis (CoMSIA) model (q² = 0.731, R² = 0.987). The systemic external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with $ R{^2}_{\!\!\!\rm pred} $ values of 0.818 and 0.892, $ {r^2}_{\!\!\!\rm m} $ values of 0.879 and 0.886, $ {r^2}_{\!\!\!\rm m(LOO)} $ values of 0.874 and 0.874, $ r^2_{\rm m(overall)} $ values of 0.879 and 0.885, respectively. Several key structural features of the compounds responsible for inhibitory activity were discussed in detail. Based on these structural factors, eight new compounds with quite higher predicted Src‐inhibitory activities have been designed and presented. We hope these theoretical results can offer some valuable references for the pharmaceutical molecular design as well as the action mechanism analysis. © 2012 Wiley Periodicals, Inc.     

本征值方法在抗氧化剂定量构效关系研究中的应用

Antioxidants are of great interest because of their involvement in many important biological and industrial processes. It is meaningful to study their structure-antioxidant activity relationship (SAAR) and design novel, efficient and low-toxicity antioxidant. In this paper, Eigen Value Analysis (EVA), a 3-dimensional quantitative structure activity relationship (3-D QSAR) method, was employed to study antioxidant SAAR. Significant relational models were obtained with all the PLS cross-validate qcv^2 values being larger than 0.5, meaning that the models have sound predictive power. Compared with other QSAR methods, EVA possesses several advantages, especially that it does not need alignment. It should be believed that EVA will be an efficient approach to SAAR.     

Investigation of the relationship of the glass‐transition temperature and the polymer structure by fuzzy set theory

Fuzzy set theory can be used to study the relationship between the glass‐transition temperature (T_g) and structure of polymers. We used the method to map this relationship and obtained T_g's for 241 polymers with a standard deviation of 20 K (the confidence bound was 90%). We also used the method to predict T_g's for 15 polymers with a standard deviation of 67 K (the confidence bound was 90%). This study demonstrates that fuzzy set theory can be effectively used for determining the quantitative structure–property relationship of polymers. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 454–459, 2002; DOI 10.1002/polb.10105     

Synthesis of Self‐Threading Bithiophenes and their Structure–Property Relationships Regarding Cyclic Side‐Chains with Atomic Precision

We have recently reported a self‐threading polythiophene as a new family of insulated molecular wires. Herein, we focused on the structure–property relationships of the unique three‐dimensional architecture of the monomer. We have synthesized nine self‐threading bithiophene monomers that have cyclic side‐chains of different size and flexibility: i.e., 21‐, 22‐, 23‐, 24‐, 26‐, and 30‐membered rings composed of paraffinic, olefinic, or alkynic chains. To investigate their structure–property relationships, ¹H NMR spectroscopy, UV absorption, and fluorescence spectroscopy measurements were conducted. We found that cyclic side‐chains define the movable range of the dihedral angle of the bithiophene backbone, thereby affecting its photophysical properties. Therefore, the ability to design a structure with atomic precision as described herein would lead to the fine‐tuning of the electronic properties of insulated molecular wires.     

Multistep Continuous‐Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands

A three‐step continuous‐flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49–94 %. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure–activity‐relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single‐digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.