Two new atom centered fragment descriptors and scoring function enhance classification of antibacterial activity

Classification of pharmacologic activity of a chemical compound is an essential step in any drug discovery process. We develop two new atom-centered fragment descriptors (vertex indices) - one based solely on topological considerations without discriminating atomor bond types, and another based on topological and electronic features. We also assess their usefulness by devising a method to rank and classify molecules with regard to their antibacterial activity. Classification performances of our method are found to be superior compared to two previous studies on large heterogeneous data sets for hit finding and hit-to-lead studies even though we use much fewer parameters. It is found that for hit finding studies topological features (simple graph) alone provide significant discriminating power, and for hit-to-lead process small but consistent improvement can be made by additionally including electronic features (colored graph). Our approach is simple, interpretable, and suitable for design of molecules as we do not use any physicochemical properties. The singular use of vertex index as descriptor, novel range based feature extraction, and rigorous statistical validation are the key elements of this study.

Synthon transferability probed with IR spectroscopy: cytosine salts as models for salts of lamivudine

Co-crystal screening of the anti-HIV drug lamivudine was carried out with dicarboxylic acids as co-formers, and three of the resulting crystalline solids, two salts and a co-crystal, were studied with SCXRD, PXRD and FTIR spectroscopy. Salts of cytosine, a molecule that incorporates critical structural features of lamivudine, with the same co-formers, were taken as model systems for IR spectroscopic studies of the synthons in the salts of lamivudine. It is shown that different systems with the same synthon show very similar spectral signatures in the regions corresponding to the synthon absorptions. This reveals again the modular nature of the supramolecular synthon.

Intermolecular interactions, charge-density distribution and the electrostatic properties of pyrazinamide anti-TB drug molecule: an experimental and theoretical charge-density study

An experimental charge-density analysis of pyrazinamide (a first line antitubercular drug) was performed using high-resolution X-ray diffraction data (sin theta/lambda)(max) = 1.1 angstrom(-1)] measured at 100 (2) K. The structure was solved by direct methods using SHELXS97 and refined by SHELXL97. The total electron density of the pyrazinamide molecule was modeled using the Hansen-Coppens multipole formalism implemented in the XD software. The topological properties of electron density determined from the experiment were compared with the theoretical results obtained from CRYSTAL09 at the B3LYP/6-31G** level of theory. The crystal structure was stabilized by N-H center dot center dot center dot N and N-H center dot center dot center dot O hydrogen bonds, in which the N3-H3B center dot center dot center dot N1 and N3-H3A center dot center dot center dot O1 interactions form two types of dimers in the crystal. Hirshfeld surface analysis was carried out to analyze the intermolecular interactions. The fingerprint plot reveals that the N center dot center dot center dot H and O center dot center dot center dot H hydrogen-bonding interactions contribute 26.1 and 18.4%, respectively, of the total Hirshfeld surface. The lattice energy of the molecule was calculated using density functional theory (B3LYP) methods with the 6-31G** basis set. The molecular electrostatic potential of the pyrazinamide molecule exhibits extended electronegative regions around O1, N1 and N2. The existence of a negative electrostatic potential (ESP) region just above the upper and lower surfaces of the pyrazine ring confirm the pi-electron cloud.

First-Principles Study of Structure, Vibrational, and Elastic Properties of Stoichiometric and Calcium-Deficient Hydroxyapatite

Hydroxyapatite (HAp), a primary constituent of human bone, is usually nonstoichiometric with varying Ca/P molar ratios, with the well-known fact that Ca deficiency can cause marked reductions in its mechanical properties. To gain insights into the mechanism of this degradation, we employ first-principles calculations based on density functional theory and determine the effects of Ca deficiency on structure, vibrational, and elastic properties of HAp. Our simulation results confirm a considerable reduction in the elastic constants of HAp due to Ca deficiency, which was experimentally reported earlier. Stress-induced transformation of the Ca-deficient defected structure into a metastable state upon the application of stress could be a reason for this. Local structural stability of HAp and Ca-deficient HAp structures is assessed with full phonon dispersion studies. Further, specific signatures in the computed vibrational spectra for Ca deficiency in HAp can be utilized in experimental characterization of different types of defected HAp.

Variability of cloud liquid water and ice over South Asia from TMI estimates

In this study, the Tropical Rainfall Measurement Mission based Microwave Imager estimates (2A12) have been used to compare and contrast the characteristics of cloud liquid water and ice over the Indian land region and the ocean surrounding it, during the premonsoon (May) and monsoon (June-September) seasons. Based on the spatial homogeneity of rainfall, we have selected five regions for our study (three over ocean, two over land). Comparison across three ocean regions suggests that the cloud liquid water (CLW) over the orographically influenced Arabian Sea (close to the Indian west coast) behaves differently from the CLW over a trapped ocean (Bay of Bengal) or an open ocean (equatorial Indian Ocean). Specifically, the Arabian Sea region shows higher liquid water for a lower range of rainfall, whereas the Bay of Bengal and the equatorial Indian Ocean show higher liquid water for a higher range of rainfall. Apart from geographic differences, we also documented seasonal differences by comparing CLW profiles between monsoon and premonsoon periods, as well as between early and peak phases of the monsoon. We find that the CLW during the lean periods of rainfall (May or June) is higher than during the peak and late monsoon season (July-September) for raining clouds. As active and break phases are important signatures of the monsoon progression, we also analysed the differences in CLW during various phases of the monsoon, namely, active, break, active-to-break and break-to-active transition phases. We find that the cloud liquid water content during the break-to-active transition phase is significantly higher than during the active-to-break transition phase over central India. We speculate that this could be attributed to higher amount of aerosol loading over this region during the break phase. We lend credence to this aerosol-CLW/rain association by comparing the central Indian CLW with that over southeast Asia (where the aerosol loading is significantly smaller) and find that in the latter region, there are no significant differences in CLW during the different phases of the monsoon. While our hypothesis needs to be further investigated with numerical models, the results presented in this study can potentially serve as a good benchmark in evaluating the performance of cloud resolving models over the Indian region.

Shape Memory Alloy based Active Chiral Composite Cells

Wing morphing is one of the emerging methodology towards improving aerodynamic efficiency of flight vehicle structures. In this paper a morphing structural element is designed and studied which has its origin in the well known chiral structures. The new aspect of design and functionality explored in this paper is that the chiral cell is actuated using thermal Shape Memory Alloy (SMA) actuator wires to provide directional motion. Such structure utilizes the potential of different actuations concepts based on actuator embedded in the chiral structure skin. This paper describes a new class of chiral cell structure with integrated SMA wire for actuation. Chiral topological constructs are obtained by considering passive and active load path decoupling and sub-optimal shape changes. Single cell of chiral honeycomb with actuators are analyzed using finite element simulation results and experiments. To this end, a multi-cell plan-form is characterized showing interesting possibilities in structural morphing applications. The applicability of the developed chiral cell to flexible wing skin, variable stiffness based design and controlling longitudinal-to-transverse stiffness ratio are discussed.

Evaluating FuncSION: A software for automated synthesis of design solutions for stimulating ideation during mechanical conceptual design

The goal of the work reported in this paper is to use automated, combinatorial synthesis to generate alternative solutions to be used as stimuli by designers for ideation. FuncSION, a computational synthesis tool that can automatically synthesize solution concepts for mechanical devices by combining building blocks from a library, is used for this purpose. The objectives of FuncSION are to help generate a variety of functional requirements for a given problem and a variety of concepts to fulfill these functions. A distinctive feature of FuncSION is its focus on automated generation of spatial configurations, an aspect rarely addressed by other computational synthesis programs. This paper provides an overview of FuncSION in terms of representation of design problems, representation of building blocks, and rules with which building blocks are combined to generate concepts at three levels of abstraction: topological, spatial, and physical. The paper then provides a detailed account of evaluating FuncSION for its effectiveness in providing stimuli for enhanced ideation.

From Selective-ID to Full-ID IBS without Random Oracles

Since its induction, the selective-identity (sID) model for identity-based cryptosystems and its relationship with various other notions of security has been extensively studied. As a result, it is a general consensus that the sID model is much weaker than the full-identity (ID) model. In this paper, we study the sID model for the particular case of identity-based signatures (IBS). The main focus is on the problem of constructing an ID-secure IBS given an sID-secure IBS without using random oracles-the so-called standard model-and with reasonable security degradation. We accomplish this by devising a generic construction which uses as black-box: i) a chameleon hash function and ii) a weakly-secure public-key signature. We argue that the resulting IBS is ID-secure but with a tightness gap of O(q(s)), where q(s) is the upper bound on the number of signature queries that the adversary is allowed to make. To the best of our knowledge, this is the first attempt at such a generic construction.

Molecular topology of three ring nematogens from C-13-H-1 dipolar couplings

Molecules in their liquid crystalline phase undergo rotational motion about the long axis of the molecule and the shape adopted by the rotating molecule plays an important role in influencing the mesophase morphology. In this context, obtaining the topology and the relative orientation of the different sub-units are important steps. For studying the liquid crystalline phase, C-13 NMR spectroscopy is a convenient method and for certain specifically designed nematogens, 2-dimensional separated local field (2D-SLF) NMR spectroscopy provides a particularly simple and straightforward means of arriving at the molecular topology. We demonstrate this approach on two three ring based nematogens designed with a phenyl or a thiophene ring at one of the termini. From the C-13-H-1 dipolar couplings of the terminal carbon obtained using the 2D-SLF NMR technique, the order parameter of the local symmetry axis of the terminal phenyl ring as well as of the long molecular axis could be easily estimated. For the thiophene nematogen, the lack of symmetry of the thiophene moiety necessitates some additional computational steps. The results indicate that the thiophene unit has its local ordering axis oriented away from the long molecular axis by a small angle, consistent with a bent structure expected in view of the thiophene geometry. The experiment also demonstrates the ability of 2D-SLF NMR to provide high resolution spectra by separation of several overlapped resonances in terms of their C-13-H-1 dipolar couplings. The results are consistent with a rod-like topology of the core of the investigated mesogens. The investigation demonstrates the potential of 2D-SLF NMR C-13 spectroscopy for obtaining atomistic level information and its utility for topological studies of different mesogens.

CANDO and the infinite drug discovery frontier

The Computational Analysis of Novel Drug Opportunities (CANDO) platform (http://protinfo.org/cando) uses similarity of compound-proteome interaction signatures to infer homology of compound/drug behavior. We constructed interaction signatures for 3733 human ingestible compounds covering 48,278 protein structures mapping to 2030 indications based on basic science methodologies to predict and analyze protein structure, function, and interactions developed by us and others. Our signature comparison and ranking approach yielded benchmarking accuracies of 12-25% for 1439 indications with at least two approved compounds. We prospectively validated 49/82 `high value' predictions from nine studies covering seven indications, with comparable or better activity to existing drugs, which serve as novel repurposed therapeutics. Our approach may be generalized to compounds beyond those approved by the FDA, and can also consider mutations in protein structures to enable personalization. Our platform provides a holistic multiscale modeling framework of complex atomic, molecular, and physiological systems with broader applications in medicine and engineering.

On entanglement entropy functionals in higher-derivative gravity theories

In arXiv:1310.5713 1] and arXiv:1310.6659 2] a formula was proposed as the entanglement entropy functional for a general higher-derivative theory of gravity, whose lagrangian consists of terms containing contractions of the Riemann tensor. In this paper, we carry out some tests of this proposal. First, we find the surface equation of motion for general four-derivative gravity theory by minimizing the holographic entanglement entropy functional resulting from this proposed formula. Then we calculate the surface equation for the same theory using the generalized gravitational entropy method of arXiv:1304.4926 3]. We find that the two do not match in their entirety. We also construct the holographic entropy functional for quasi-topological gravity, which is a six-derivative gravity theory. We find that this functional gives the correct universal terms. However, as in the R-2 case, the generalized gravitational entropy method applied to this theory does not give exactly the surface equation of motion coming from minimizing the entropy functional.

Impact of Stone-Wales and lattice vacancy defects on the electro-thermal transport of the free standing structure of metallic ZGNR

We report the effect of topological as well as lattice vacancy defects on the electro-thermal transport properties of the metallic zigzag graphene nano ribbons at their ballistic limit. We employ the density function theory-Non equilibrium green's function combination to calculate the transmission details. We then present an elaborated study considering the variation in the electrical current and the heat current transport with the change in temperature as well as the voltage gradient across the nano ribbons. The comparative analysis shows, that in the case of topological defects, such as the Stone-Wales defect, the electrical current transport is minimum. Besides, for the voltage gradient of 0.5 Volt and the temperature gradient of 300 K, the heat current transport reduces by similar to 62 % and similar to 50% for the cases of Stones-Wales defect and lattice vacancy defect respectively, compared to that of the perfect one.

Characterization of Interactions Involving Bromine in 2,2-Dibromo2,3-dihydroinden-1-one via Experimental Charge Density Analysis

Experimental and theoretical charge density analyses on 2,2-dibromo-2,3-dihydroinden-1-one have been carried out to quantify the topological features of a short CBr....O halogen bond with nearly linear geometry (2.922 angstrom, angle CBr....O = 172.7 degrees) and to assess the strength of the interactions using the topological features of the electron density. The electrostatic potential map indicates the presence of the s-hole on bromine, while the interaction energy is comparable to that of a moderate OH....O hydrogen bond. In addition, the energetic contribution of CH.....Br interaction is demonstrated to be on par with that of the CBr....O halogen bond in stabilizing the crystal structure.

Computational Study of the Formation of Short Centrosymmetric N-center dot center dot center dot S Supramolecular Synthon and Related Weak Interactions in Crystalline 1,2,4-Triazoles

A comprehensive analysis of the crystal packing and the energetic features of a series of four biologically active molecules belonging to the family of substituted 4-(benzylideneamino)-3-(4-fluoro-3-phenoxyphenyl)-1H-1,2,4-triazole-5-(4 H)-thione derivatives have been performed based on the molecular conformation and the supramolecular packing. This involves the formation of a short centrosymmetric R-2(2)(8) NH...S supramolecular synthon in the solid state, including the presence of CH...S, CH...O, CH...N, CH...F, CH...Cl, CF...FC, CCl...ClC, and CH...pi intermolecular interactions along with pp stacking to evaluate the role of noncovalent interactions in the crystal. The presence of such synthons has a substantial contribution toward the interaction energy (-18 to -20 kcal/mol) as obtained from the PIXEL calculation, wherein the Coulombic and polarization contribution are more significant than the dispersion contribution. The geometrical characteristics of such synthons favor short distance, and the population of related molecules having these geometries is rare as has been obtained from the Cambridge Structural Database (CSD). Furthermore, their interaction energies have been compared with those present in our molecules in the solid state. The topological characteristics of the NH...S supramolecular synthon, in addition to related weak interactions, CH...N, CH...Cl, CF...FC, and CCl...ClC, have been estimated using the quantum theory of atoms in molecules (QTAIM). In addition, an analysis of the Hirshfeld surface and associated fingerprint plots of these four molecules also have provided a platform for the evaluation of the contribution of different atom...atom contacts, which contribute toward the packing of the molecules in solids.

Multiscale Symmetry Detection in Scalar Fields by Clustering Contours

The complexity in visualizing volumetric data often limits the scope of direct exploration of scalar fields. Isocontour extraction is a popular method for exploring scalar fields because of its simplicity in presenting features in the data. In this paper, we present a novel representation of contours with the aim of studying the similarity relationship between the contours. The representation maps contours to points in a high-dimensional transformation-invariant descriptor space. We leverage the power of this representation to design a clustering based algorithm for detecting symmetric regions in a scalar field. Symmetry detection is a challenging problem because it demands both segmentation of the data and identification of transformation invariant segments. While the former task can be addressed using topological analysis of scalar fields, the latter requires geometry based solutions. Our approach combines the two by utilizing the contour tree for segmenting the data and the descriptor space for determining transformation invariance. We discuss two applications, query driven exploration and asymmetry visualization, that demonstrate the effectiveness of the approach.