A comparison of field-based similarity searching methods: CatShape, FBSS, and ROCS

Three field-based similarity methods are compared in retrospective virtual screening experiments. The methods are the CatShape module of CATALYST, ROCS, and an in-house program developed at the University of Sheffield called FBSS. The programs are used in both rigid and flexible searches carried out in the MDL Drug Data Report. UNITY 2D fingerprints are also used to provide a comparison with a more traditional approach to similarity searching, and similarity based on simple whole-molecule properties is used to provide a baseline for the more sophisticated searches. Overall, UNITY 2D fingerprints and ROCS with the chemical force field option gave comparable performance and were superior to the shape-only 3D methods. When the flexible methods were compared with the rigid methods, it was generally found that the flexible methods gave slightly better results than their respective rigid methods; however, the increased performance did not justify the additional computational cost required.     

Application of belief theory to similarity data fusion for use in analog searching and lead hopping

A wide variety of computational algorithms have been developed that strive to capture the chemical similarity between two compounds for use in virtual screening and lead discovery. One limitation of such approaches is that, while a returned similarity value reflects the perceived degree of relatedness between any two compounds, there is no direct correlation between this value and the expectation or confidence that any two molecules will in fact be equally active. A lack of a common framework for interpretation of similarity measures also confounds the reliable fusion of information from different algorithms. Here, we present a probabilistic framework for interpreting similarity measures that directly correlates the similarity value to a quantitative expectation that two molecules will in fact be equipotent. The approach is based on extensive benchmarking of 10 different similarity methods (MACCS keys, Daylight fingerprints, maximum common subgraphs, rapid overlay of chemical structures (ROCS) shape similarity, and six connectivity-based fingerprints) against a database of more than 150,000 compounds with activity data against 23 protein targets. Given this unified and probabilistic framework for interpreting chemical similarity, principles derived from decision theory can then be applied to combine the evidence from different similarity measures in such a way that both capitalizes on the strengths of the individual approaches and maintains a quantitative estimate of the likelihood that any two molecules will exhibit similar biological activity.     

New methods for ligand-based virtual screening: use of data fusion and machine learning to enhance the effectiveness of similarity searching

Similarity searching using a single bioactive reference structure is a well-established technique for accessing chemical structure databases. This paper describes two extensions of the basic approach. First, we discuss the use of group fusion to combine the results of similarity searches when multiple reference structures are available. We demonstrate that this technique is notably more effective than conventional similarity searching in scaffold-hopping searches for structurally diverse sets of active molecules; conversely, the technique will do little to improve the search performance if the actives are structurally homogeneous. Second, we make the assumption that the nearest neighbors resulting from a similarity search, using a single bioactive reference structure, are also active and use this assumption to implement approximate forms of group fusion, substructural analysis, and binary kernel discrimination. This approach, called turbo similarity searching, is notably more effective than conventional similarity searching.     

Antiviral drug nevirapine as a template for hydrated imidazoline ring expansion (HIRE): Rapid access to the diarene-fused 1,4,7-triazecine ring system

The tricyclic ring system of the antiviral drug nevirapine has been employed to test the workability of the hydrated imidazoline ring expansion (HIRE) reaction which was previously exemplified for [1.4]oxazepine and [1.4]thiazepine counterparts. The imidazoline nucleus was grafted onto the lactam moiety of nevirapine in two high-yielding steps. Subsequent N-alkylation and the HIRE reaction proceeded as envisioned and delivered rare ring-expanded diarene-fused 1,4,7-triazecines with a diversity of alkyl substituents at the lactam nitrogen atom. These findings extend the scope of the HIRE reaction to the medicinally prominent [1.4]diazepine chemical space.     

Fe(NO3)3 as an efficient catalyst for regio- and stereo-controlled ring expansion of 1,2-diaroyl-3-arylaziridines

Several 1,2-diaroyl-3-arylaziridines were previously prepared conveniently and used in the preparation of 5-benzoyl-2,4-diaryl oxazolines in the presence of NaI. In this work, synthesis of some trans-4-benzoyl-2,5-diaryl oxazolines by a regio- and stereo-controlled reaction in the presence of Iron (III) nitrate at room temperature is reported. A plausible mechanism has been proposed for ring expansion of N-acyl aziridines to oxazolines.     

Quantitative molecular similarity analysis (QMSA) methods for property estimation: a comparison of property-based,arbitrary, and tailored similarity spaces

Three classes of arbitrary quantitative molecular similarity analysis (QMSA) methods have been computed using atom pairs, topological indices, and physicochemical properties. Tailored QMSA models have been developed using a selected number of TIs chosen by ridge regression. The methods have been applied to the K-nearest neighbor based estimation of log P of two sets of chemicals. Results show that the property-based and tailored QMSA methods are superior to the arbitrary similarity methods in estimating log P of both sets of chemicals     

Quantitative molecular similarity analysis (QMSA) methods for property estimation: A comparison of property-based,arbitrary, and tailored similarity spaces

Three classes of arbitrary quantitative molecular similarity analysis (QMSA) methods have been computed using atom pairs, topological indices, and physicochemical properties. Tailored QMSA models have been developed using a selected number of TIs chosen by ridge regression. The methods have been applied to the K -nearest neighbor based estimation of log P of two sets of chemicals. Results show that the property-based and tailored QMSA methods are superior to the arbitrary similarity methods in estimating log P of both sets of chemicals     

Fitted electronic density functions from H to Rn for use in quantum similarity measures: cis-diamminedichloroplatinum(II) complex as an application example

A consistent set of fitted electronic density functions was generated for the elements from hydrogen to radon using an algorithm based on the elementary Jacobi rotations (EJR) technique. The main distinguishing attribute of this fitting procedure is the production of approximated electronic density functions with positive definite expansion coefficients; in this way, the statistical meaning of the probability distribution is preserved. The methodology, which was fully described previously, was modified in this work to improve and accelerate the fitting procedure. This variation concerns the optimization method employed to obtain the optimal angle of the EJR, implementing an algorithm based on a Taylor series expansion. Additionally, a new 1S-Type Gaussian basis set for atoms H to Rn is presented, that was fitted from a primitive basis set of Huzinaga. Fitted density functions facilitate theoretical calculations over large molecules and may be employed in many areas of computational chemistry, for example, in quantum similarity measures (QSM). To verify the basis set, a sound example related to QSM applications is given. This corresponds to the comparison of experimental structures obtained from X-ray determination for cis-diamminedichloroplatinum(II) complex with optimized molecular geometries using several theoretical methods to quantify the differences between the analyzed levels of theory. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 911–920, 1999     

Enantioselective synthesis of natural mesembrine using (D)-mannitol as a chiral template,a model study for the enantioselective synthesis of the amaryllidaceae alkaloids

Enantioselective synthesis of (?)-mesembrine(1) has been achieved using (D)-mannitol with the intention of developing the enantioselective synthesis of the Amaryllidaceae alkaloids.     

Al2O3(1120) surface as a template for the ordered growth of Ni and Co nanoclusters

The morphology and thermal stability of Ni and Co nanoclusters grown by physical vapour deposition on a reconstructed (1120) surface of α-Al(2)O(3) is investigated using non-contact atomic force microscopy (NC-AFM). NC-AFM images reveal that the clean α-Al(2)O(3)(1120) substrate adopts a characteristic (12 × 4) reconstruction when prepared in vacuum at high temperature. Subsequent deposition of Ni and Co onto this substrate at room temperature facilitates the growth of well-ordered metal nanocluster arrays with a preferred inter-cluster distance determined by the (12 × 4) periodicity of the substrate surface. The order in the cluster arrangement remains intact even upon annealing the system to temperatures up to 500 °C indicating a high resistance against sintering. The reconstructed α-Al(2)O(3)(1120) surface can, therefore, serve as an appropriate insulating template for studies of size-dependent magnetic or catalytic effects in a well-defined ensemble of metallic nanoclusters.     

Structure of the human telomere in K+ solution: an intramolecular (3 + 1) G-quadruplex scaffold

We present the intramolecular G-quadruplex structure of human telomeric DNA in physiologically relevant K(+) solution. This G-quadruplex, whose (3 + 1) topology differs from folds reported previously in Na(+) solution and in a K(+)-containing crystal, involves the following: one anti.syn.syn.syn and two syn.anti.anti.anti G-tetrads; one double-chain reversal and two edgewise loops; three G-tracts oriented in one direction and the fourth in the opposite direction. The topological characteristics of this (3 + 1) G-quadruplex scaffold should provide a unique platform for structure-based anticancer drug design targeted to human telomeric DNA.     

The use of metalloids (-SiMe3,-SnR3) as protected carbanions : Selective activation and new cyclization processes

Two aspects of organosilicon and -tin chemistry will be dealt with in this paper: the reactivity of allylmetalloids and the potential of the C-MR₃ function as a protected carbanion which can be unmasked to provide synthetically useful carbon nucleophiles with the primary focus on the latter.     

Communication: rigorous calculation of dissociation energies (D0) of the water trimer, (H2O)3 and (D2O)3

Using a recent, full-dimensional, ab initio potential energy surface [Y. Wang, X. Huang, B. C. Shepler, B. J. Braams, and J. M. Bowman, J. Chem. Phys. 134, 094509 (2011)] together with rigorous diffusion Monte Carlo calculations of the zero-point energy of the water trimer, we report dissociation energies, D(0), to form one monomer plus the water dimer and three monomers. The calculations make use of essentially exact zero-point energies for the water trimer, dimer, and monomer, and benchmark values of the electronic dissociation energies, D(e), of the water trimer [J. A. Anderson, K. Crager, L. Fedoroff, and G. S. Tschumper, J. Chem. Phys. 121, 11023 (2004)]. The D(0) results are 3855 and 2726 cm(-1) for the 3H(2)O and H(2)O + (H(2)O)(2) dissociation channels, respectively, and 4206 and 2947 cm(-1) for 3D(2)O and D(2)O + (D(2)O)(2) dissociation channels, respectively. The results have estimated uncertainties of 20 and 30 cm(-1) for the monomer plus dimer and three monomer of dissociation channels, respectively.     

CF3CH(ONO)CF3: Synthesis,IR spectrum,and use as OH radical source for kinetic and mechanistic studies

The synthesis, IR spectrum, and first‐principles characterization of CF₃CH(ONO)CF₃ as well as its use as an OH radical source in kinetic and mechanistic studies are reported. CF₃CH(ONO)CF₃ exists in two conformers corresponding to rotation about the RCO? NO bond. The more prevalent trans conformer accounts for the prominent IR absorption features at frequencies (cm^?1) of 1766 (N?O stretch), 1302, 1210, and 1119 (C? F stretches), and 761 (O? N? O bend); the cis conformer contributes a number of distinct weaker features. CF₃CH(ONO)CF₃ was readily photolyzed using fluorescent blacklamps to generate CF₃C(O)CF₃ and, by implication, OH radicals in 100% yield. CF₃CH(ONO)CF₃ photolysis is a convenient source of OH radicals in the studies of the yields of CO, CO₂, HCHO, and HC(O)OH products which can be difficult to measure using more conventional OH radical sources (e.g., CH₃ONO photolysis). CF₃CH(ONO)CF₃ photolysis was used to measure k(OH + C₂H₄)/k(OH + C₃H₆) = 0.29 ± 0.01 and to establish upper limits of 16 and 6% for the molar yields of CO and HC(O)OH from the reaction of OH radicals with benzene in 700 Torr of air at 296 K. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 159–165, 2003     

Forging of nicotine for the effective management of diabetic wounds: A hybrid of scaffold hopping and molecular dynamics simulation approaches

Diabetic wound (DW) is a huge threat to the health care community and is always challenging to treat. The main biochemical culprits in DW recalcitrance are elevated inflammatory mediators, proteases, cell proliferation and migration suppressors, anti-angiogenic factors, and bacterial infections. In this scenario, using a scaffold to target important factors at each stage of pathogenesis can accelerate the healing process. Many shreds of evidence disclosed the role of nicotine scaffold in handling inflammation, infection, proliferation, migration, and angiogenesis. All these factors made us forge nicotine by employing a scaffold hopping approach. The hops were then subjected to molecular docking and binding free energy calculations against Matrix metallopeptidase 9, Glycogen synthase kinase 3 beta, Tumor necrosis factor alpha, MurC and ParE enzymes. Gratifyingly, molecule H1 was found to possess significant inhibitory activity against the selected receptors as evidenced by their high negative glide score and binding energy. Furthermore, 100 ns of molecular dynamics simulation studies (MD) was performed for the five H1/4XCT, H1/5F95, H1/2AZ5, H1/4C13 and H1/4MOT complexes to get insight into the binding modes and stability. The MD results showed significant stability as evidenced by the low conformational changes of the H1 with the chosen receptors. Hence, H1 might be a druggable candidate in the therapeutic management of DW. However, further research is strongly recommended to advance the drug into the therapeutic pipeline.     

TREN (Tris(2-aminoethyl)amine): an effective scaffold for the assembly of triple helical collagen mimetic structures

A new scaffold, TREN-(suc-OH)(3) where TREN is tris(2-aminoethyl)amine and suc is the succinic acid spacers, was incorporated to assemble triple helices composed of Gly-Nleu-Pro sequences (Nleu denotes N-isobutylglycine). Extensive biophysical studies which include denaturation studies, CD and NMR spectroscopy, and molecular modeling demonstrated that TREN-[suc-(Gly-Nleu-Pro)(n)-NH(2)](3) (n = 5 and 6) form stable triple helical structures in solution. A comparative analysis of TREN-assembled and KTA-assembled collagen mimetics (KTA denotes Kemp triacid, 1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid) indicates that the flexibility of the TREN scaffold is superior to the KTA scaffold in inducing triple helicity. This effect most likely arises from the flexibility of the TREN scaffold which allows the three peptide chains to adjust their register for a tighter triple helical packing.     

Borate Hydrides as a New Material Class: Structure,Computational Studies,and Spectroscopic Investigations on Sr5(BO3)3H and Sr5(11BO3)3D

The unprecedented borate hydride Sr₅(BO₃)₃H and deuteride Sr₅(¹¹BO₃)₃D crystallizing in an apatite-related structure are reported. Despite the presence of hydride anions, the compound decomposes only slowly in air. Doped with Eu²⁺, it shows broad-band orange-red emission under violet excitation owing to the 4f⁶5d–4f⁷ transition of Eu²⁺. The observed ¹H NMR chemical shift is in good agreement with previously reported ¹H chemical shifts of ionic metal hydrides as well as with quantum chemical calculations and very different from ¹H chemical shifts usually found for hydroxide ions in similar materials. FTIR and Raman spectroscopy of different samples containing ¹H, ²H, ^natB, and ¹¹B combined with calculations unambiguously prove the absence of hydroxide ions and the sole incorporation of hydride ions into the borate. The orange-red emission obtained by doping with Eu²⁺ shows that the new compound class might be a promising host material for optical applications.     

Calcined Mg-Fe-CO(3) LDH as an adsorbent for the removal of selenite

Mg-Fe-CO(3) layered double hydroxide (LDH) with a Mg/Fe molar ratio of 2.0 was synthesized by co-precipitation method and its calcined product (CLDH) was obtained by heating Mg/Fe-LDH at 500 degrees C. Sorption of SeO(2-)(3) on CLDHs was studied and the results indicate that the sorption capacity of CLDHs was higher than that of uncalcined LDHs. Isotherms for SeO(2-)(3) sorption by CLDHs were well described using the Freundlich and Langmuir equations. The thermodynamic parameters, viz. DeltaG*, DeltaH*, DeltaS* were calculated to predict the nature of adsorption. The negative and positive values of DeltaG* and DeltaH* indicate that the adsorption process is spontaneous and endothermic in nature, respectively. The adsorption process followed first-order kinetics.