Prediction of activity cliffs on the basis of images using convolutional neural networks

An activity cliff (AC) is formed by a pair of structurally similar compounds with a large difference in potency. Accordingly, ACs reveal structure–activity relationship (SAR) discontinuity and provide SAR information for compound optimization. Herein, we have investigated the question if ACs could be predicted from image data. Therefore, pairs of structural analogs were extracted from different compound activity classes that formed or did not form ACs. From these compound pairs, consistently formatted images were generated. Image sets were used to train and test convolutional neural network (CNN) models to systematically distinguish between ACs and non-ACs. The CNN models were found to predict ACs with overall high accuracy, as assessed using alternative performance measures, hence establishing proof-of-principle. Moreover, gradient weights from convolutional layers were mapped to test compounds and identified characteristic structural features that contributed to successful predictions. Weight-based feature visualization revealed the ability of CNN models to learn chemistry from images at a high level of resolution and aided in the interpretation of model decisions with intrinsic black box character.

     

Different binding modes of structurally diverse ligands for human D3DAR

Five different dopamine D3 receptors (D3DARs) models were created considering some suggested binding modes for D3DAR antagonists reported in earlier computational studies. Different hypotheses are justified because of the lack of experimental information about the putative site of interaction and are also due to the variability in scaffolds and size of D3DAR ligands. In this study 114 potent and selective D3DAR antagonists or partial agonists are used as key experimental information to discriminate the most reliable receptor model and to build a docking based 3D quantitative structure-activity relationship model able to indicate the ligand properties and the residues important for activity. The ability of this D3DAR model to discriminate the binding mode of different classes of ligands, showing a good quantitative correlation with their activity, encourages us to use it for screening novel lead compounds.     

Systematic identification and classification of three-dimensional activity cliffs

Activity cliffs were systematically extracted from public domain X-ray structures of targets for which complexes with multiple ligands were available, following the concept of three-dimensional (3D) cliffs. Binding modes of ligands with well-defined potency measurements were compared in a pairwise manner, and their 3D similarity was calculated using a previously reported property density function-based method taking conformational, positional, and chemical differences into account. Requiring the presence of at least 80% 3D similarity and a potency difference of at least 2 orders of magnitude as cliff criteria, a total of 216 well-defined 3D activity cliffs were detected in the Protein Data Bank (PDB). These 3D-cliffs involved a total of 269 ligands active against 38 different targets belonging to 17 protein families. For 255 of these compounds, binding modes were available at high crystallographic resolution. All 3D-cliffs were analyzed in detail and assigned to different categories on the basis of crystallographic interaction patterns. In many instances, differences in ligand-target interactions suggested plausible causes for origins of 3D-cliffs. In other cases, short-range interactions seen in X-ray structures were insufficient to deduce possible reasons for cliff formation. The 3D-cliffs described herein further advance the rationalization of activity cliffs at the level of ligand-target interactions and should also be useful for other applications such as the calibration of energy functions for structure-based design. The pool of identified activity cliffs is provided to enable subsequent structure-based analyses of cliffs.     

Dual-frequency 2D IR on interaction of weak and strong IR modes

Dual-frequency 2D IR heterodyne photon-echo spectroscopy of C[triple bond]N and C=O stretching vibrational modes in 2-cyanocoumarin is reported. We have shown that the interaction among these modes provides convenient and useful structural constraints for molecules. Implementation of two pulse sequences, 4, 4, and 6 microm and 6, 6, and 4 microm, allowed the clear determination of contributions caused by vibrational relaxation. Positive correlation between C[triple bond]N and C=O frequency distributions was observed in 2-cyanocoumarin. Because C[triple bond]N modes are highly localized and have frequencies in a spectral region with minimal water absorption, the C[triple bond]N/C=O interactions have a strong potential for use as structural reporters in proteins. In addition to CN/CO peaks, the cross-peaks responsible for the C[triple bond]N/C=C interaction are also observed in the 2D IR spectra, where C=C is a coumarin ring stretching mode. We have demonstrated that 2D IR spectroscopy can utilize interactions of strong IR modes with weak local modes as structural reporters.     

An efficient sensor for Zn2+ and Cu2+ based on different binding modes

An efficient sensor for Zn(2+) and Cu(2+) was designed based on different binding modes. The sensor displays ratiometric signals for Zn(2+), due to the Zn(2+)-triggered amide tautomerization; while dual-mode selective behaviors for Cu(2+) result from the deprotonation of the amide tautomer.     

New syntheses on the basis of ethyl 2-oxotetrahydrofuran-3-carboxylates

Alkylation of 5-substituted ethyl 5-methyl-2-oxotetrahydrofuran-3-carboxylates with alkyl halides in the presence of sodium ethoxide gave the corresponding 3-alkyl derivatives which were converted into 3,5-substituted 5-methyl-N-(4-nitrophenyl)-2-oxotetrahydrofuran-3-carboxamides and 5-methyltetrahydrofuran-2-ones. Reactions of the latter with hydrazine hydrate led to the formation of 4-hydroxypentanoic acid hydrazides which were treated with isothiocyanates to obtain the corresponding thiosemicarbazides whose intramolecular cyclization in the presence of aqueous alkali gave previously unknown 1,2,4-triazole-3-thiol derivatives.     

Dynamics of amide-I modes of the alanine dipeptide in D2O

The equilibrium dynamics of the acetyl and amino amide-I groups of the alanine dipeptide were examined separately using (13)C isotopic selection and 2D IR. The population relaxation times of the amide transitions were measured to be in the range 500 fs by means of heterodyne transient grating methods. The vibrational frequency correlation functions consisted in all cases of a motionally narrowed part, a component near 800 fs, and a constant part representing a distribution of structures that is static on the few ps time scale. The intermediate time scale is attributed to fluctuations in the stretching and bending of hydrogen bonds between the carbonyl and water.     

Cu2+ binding modes of recombinant alpha-synuclein--insights from EPR spectroscopy

The interaction of the small (140 amino acid) protein, alpha-synuclein (alphaS), with Cu(2+) has been proposed to play a role in Parkinson's disease (PD). While some insight from truncated model complexes has been gained, the nature of the corresponding Cu(2+) binding modes in the full length protein remains comparatively less well characterized. This work examined the Cu(2+) binding of recombinant human alphaS using Electron Paramagnetic Resonance (EPR) spectroscopy. Wild type (wt) alphaS was shown to bind stoichiometric Cu(2+) via two N-terminal binding modes at physiological pH. An H50N mutation isolated one binding mode, whose g parallel, A parallel, and metal-ligand hyperfine parameters correlated well with a {NH2, N(-), beta-COO(-), H2O} mode previously identified in truncated model fragments. Electron spin-echo envelope modulation (ESEEM) studies of wt alphaS confirmed the second binding mode at pH 7.4 involved coordination of His50 and its g parallel and A parallel parameters correlated with either {NH2, N(-), beta-COO(-), N(Im)} or {N(Im), 2 N(-)} coordination observed in alphaS fragments. At pH 5.0, His50-anchored Cu(2+) binding was greatly diminished, while {NH2, N(-), beta-COO(-), H2O} binding persisted in conjunction with another two binding modes. Metal-ligand hyperfine interactions from one of these indicated a 1N3O coordination sphere, which was ascribed to a {NH2, CO} binding mode. The other was characterized by a spectrum similar to that previously observed for diethylpyrocarbonate-treated alphaS and was attributed to C-terminal binding centered on Asp121. In total, four Cu(2+) binding modes were identified within pH 5.0-7.4, providing a more comprehensive picture of the Cu(2+) binding properties of recombinant alphaS.     

Collective plasmon modes excited on a silver nanoparticle 2D crystalline sheet

This paper describes unique plasmonic characteristics of two dimensional (2D) crystalline sheets composed of homogeneous Ag nanoparticles (AgNPs) fabricated by the Langmuir-Schaefer method at an air-water interface. The localized surface plasmon resonance (LSPR) band of the Ag nanosheet was tuned by changing the interparticle distance of AgNPs via the length of the organic capping molecules. Red shift of the LSPR band of the AgNPs sheet followed an exponential law against the interparticle distance in a similar manner to the previous reports of metal nanodisc pairs. However, the shift was much larger and less dependent on the interparticle separation gap. This phenomenon is reasonably interpreted as the long-range interaction of LSPR in the 2D sheet ('delocalized' LSPR) confirmed by simulation using the finite difference time domain (FDTD) method. The FDTD simulation also revealed additional enhancement of local electric fields on the 2D sheet compared to those on the single or paired particles.     

Synthesis of macroheterocyclic compounds on the basis of 3-chloro-2-hydrazinoquinoxaline

2-Amino-1-[(3-chloro-2-quinoxalinyl)azo]naphthalene was obtained by oxidative coupling of 3-chloro-2-hydrazinoquinoxaline with 2-aminonaphthalenesulfonic acid; cross self-cyclization of the product was used to synthesize macrocyclic compounds, viz., [1,2,5,8,9,12]hexaazacyclotetradecene derivatives. 4-[(3-Chloro-2-quinoxalinyl)azo]-5-chloro-3-methyl-1-phenylpyrazole was obtained by the reaction of the 4-(3-chloro-2-quinoxalinyl)hydrazone of 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazole-3,4-dione with POCl₃. Reaction of this product with 2,2-diaminoazobenzene under standard conditions gave [1,2,5,8,9,12]-hexaazacyclotetradecene derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 546–551, April, 1981.     

The structure of the compound Cd3P2

Structure of Cd₃P₂ (P4₂/nmc, a = b = 8.7390 Å, c = 12.2523 Å) has been solved and refined up to R = 3.78% using precision X-ray diffraction experimental data (λ-MoK _α, graphite monochromator on a primary beam, 11529 reflections). Interatomic distances and valence angles are determined. Phosphorus forms a face-centered cubic lattice in which 3/4 tetrahedral voids are occupied by cadmium atoms in the crystal structure. The structure can be described by two equivalent models in which the positions of cadmium atoms, which occupy tetrahedral voids following the “diamond principle,” are preserved, while the remaining free and occupied voids change their places.     

Exploration of the Ca2+ interaction modes of the nifedipine calcium channel antagonist.

A comprehensive study is carried out using quantum chemical computation and molecular dynamics (MD) simulations to gain insight into the interaction between Ca(2+) ions and the most important class of calcium channel antagonists--nifedipine. First, the chelating structures and energetic characters of nifedipine-Ca(2+) in the gas phase are explored, and 25 isomers are found. The most favorable chelating mode is a tridentate one, that is, Ca(2+) binds to two carbonyl O atoms and one nitryl O atom, where Ca(2+) is above the plane of the three O atoms to form a pyramidal structure. Accurate geometric structures, relative stabilities, vertical and adiabatic binding energies, and charge distributions are discussed. The differences in the geometries and energies among these isomers are analyzed from the contributions of chelating sites, electrostatics and polarizations, steric repulsions, and charge distributions. The interconversions among isomers with similar geometries and energies are also investigated because of the importance of the geometric transformation in the biological system. Furthermore, certain numbers of water molecules are added to the nifedipine-Ca(2+) system to probe the effect of water. A detailed study is performed on the hydrated geometries on the basis of the most stable isomer 1. Stepwise hydration can weaken the nifedipine-Ca(2+) interaction, and the chelating sites of nifedipine are gradually replaced by the added water molecules. Hexacoordination is found to be the most favorable geometry no matter how many water molecules were added, which can be verified by the MD simulations. The transfer of water molecules from the inner shell to the outer shell is also supported by MD simulations of the hexahydrated complexes.     

Lifetime measurements of the 3D3/2 and 3D5/2 metastable states in CaII

The lifetime of the metastable 3D_3/2 and 3D_5/2 states of Ca⁺ ions is determined in a r.f. ion trap by laser excitation of this levels and subsequent time delayed probing of the state population by a second laser. In a buffer gas atmosphere of about 10^–5–10^–6 mbar of He we observe quenching to the ground state and strong finestructure mixing of the two D-states. This mixing allowes only the determination of the combined lifetime. Our result of (3D)=1.24(39) s is in good agreement with theoretical calculations.     

二维无机-有机化合物的晶体结构及紫外研究

通过水热方法合成了二维无机-有机杂化化合物Co3(fcz)4(V3O9)2.2H2O.单晶X射线衍射分析表明化合物结晶于三斜晶系,P-1空间群.(V3O9)3-多阴离子连接Co(1)离子形成了金属氧链,该链进一步通过连接Co(2)离子形成二维无机层.fcz分子以双单齿的配位方式配位到同一个二维层的2个金属离子上,使化合物最终展示了二维结构.此外,还研究了该化合物固体的紫外-可见漫反射光谱.     

Synthesis and biological evaluation of all A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) and their 20-epimers: possible binding modes of potent A-ring analogues to vitamin D receptor.

BACKGROUND: The secosteroid 1 alpha,25-dihydroxyvitamin D(3) (1) has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insight into the structure-activity relationships of the A-ring of 1 is still needed to assist the development of more potent and selective analogues as candidate chemotherapeutic agents, as well as to define the molecular mode of action. RESULTS: All possible A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D(3) (6a-h) and their 20-epimers (7a-h) were designed and efficiently synthesized. The dependence of the affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), as well as the HL-60 cell differentiation-inducing activity, upon the stereochemistry of the A-ring and at C20 in the side chain was evaluated. CONCLUSIONS: The binding affinities and potency of the 5,6-trans and 5,6-cis analogues were enhanced by a 2-methyl substituent in a certain orientation. Molecular docking studies based upon the X-ray crystal structure of VDR suggested that the axial 2-methyl group would be accommodated in a pocket surrounded by hydrophobic amino acid residues in the ligand binding domain, resulting in enhanced interaction.     

2D/2D BiOBr/g-C3N4 S型异质结光催化性能

近年来,能源短缺和环境污染严重威胁人类的可持续发展.光催化技术具有绿色环保、成本低等优势,被认为是解决上述问题的最佳途径之一,其实用化的核心是开发高效可见光催化材料.石墨相氮化碳(g-C3N4)因其物理化学性质稳定、无毒、廉价及能带适宜等特点,广泛应用于光催化领域.然而,光生载流子易复合、比表面积小等问题不利于其实际应...     

Predicting bioactive conformations and binding modes of macrocycles

Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein–protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction. Herein, we report predictions of bioactive conformations of macrocycles using conformational search and binding modes using docking. Conformational ensembles generated using specialized search technique of about 70 % of the tested macrocycles contained accurate bioactive conformations. However, these conformations were difficult to identify on the basis of conformational energies. Moreover, docking calculations with limited ligand flexibility starting from individual low energy conformations rarely yielded highly accurate binding modes. In about 40 % of the test cases, binding modes were approximated with reasonable accuracy. However, when conformational ensembles were subjected to rigid body docking, an increase in meaningful binding mode predictions to more than 50 % of the test cases was observed. Electrostatic effects did not contribute to these predictions in a positive or negative manner. Rather, achieving shape complementarity at macrocycle-target interfaces was a decisive factor. In summary, a combined computational protocol using pre-computed conformational ensembles of macrocycles as a starting point for docking shows promise in modeling binding modes of macrocyclic compounds.