Kinetic model construction using chemoinformatics

Kinetic models of chemical processes not only provide an alternative to costly experiments; they also have the potential to accelerate the pace of innovation in developing new chemical processes or in improving existing ones. Kinetic models are most powerful when they reflect the underlying chemistry by incorporating elementary pathways between individual molecules. The downside of this high level of detail is that the complexity and size of the models also steadily increase, such that the models eventually become too difficult to be manually constructed. Instead, computers are programmed to automate the construction of these models, and make use of graph theory to translate chemical entities such as molecules and reactions into computer-understandable representations. This work studies the use of automated methods to construct kinetic models. More particularly, the need to account for the three-dimensional arrangement of atoms in molecules and reactions of kinetic models is investigated and illustrated by two case studies. First of all, the thermal rearrangement of two monoterpenoids, cis- and trans-2-pinanol, is studied. A kinetic model that accounts for the differences in reactivity and selectivity of both pinanol diastereomers is proposed. Secondly, a kinetic model for the pyrolysis of the fuel “JP-10” is constructed and highlights the use of state-of-the-art techniques for the automated estimation of thermochemistry of polycyclic molecules. A new code is developed for the automated construction of kinetic models and takes advantage of the advances made in the field of chemo-informatics to tackle fundamental issues of previous approaches. Novel algorithms are developed for three important aspects of automated construction of kinetic models: the estimation of symmetry of molecules and reactions, the incorporation of stereochemistry in kinetic models, and the estimation of thermochemical and kinetic data using scalable structure-property methods. Finally, the application of the code is illustrated by the automated construction of a kinetic model for alkylsulfide pyrolysis

Research and Technology 1995

This report selectively summarizes the NASA Lewis Research Center's research and technology accomplishments for fiscal year 1995. It comprises over 150 short articles submitted by the staff members of the technical directorates. The report is organized into six major sections: aeronautics, aerospace technology, space flight systems, engineering support, Lewis Research Academy, and technology transfer. A table of contents, an author index, and a list of NASA Headquarters program offices have been included to assist the reader in finding articles of special interest. This report is not intended to be a comprehensive summary of all research and technology work done over the past fiscal year. Most of the work is reported in Lewis-published technical reports, journal articles, and presentations prepared by Lewis staff members and contractors (for abstracts of these Lewis-authored reports, visit the Lewis Technical Report Server (LETRS) on the World Wide Web-http://letrs.lerc.nasa.gov/LeTRS/). In addition, university grants have enabled faculty members and graduate students to engage in sponsored research that is reported at technical meetings or in journal articles. For each article in this report, a Lewis contact person has been identified, and where possible, reference documents are listed so that additional information can be easily obtained. The diversity of topics attests to the breadth of research and technology being pursued and to the skill mix of the staff that makes it possible. For more information about Lewis' research, visit us on the World Wide web-http://www.lerc.nasa.gov

Computer-Aided Design of Ligands at Multiple Protein Targets for Multifactorial Diseases

Today, drug discovery predominately focuses on the design of ligands with high selectivity towards a specific biological target. A significant limitation in the case of multi-factorial diseases (e.g. neurodegenerative disorders) is that effective therapy may require multi-target drugs addressing the complexity of multi-factorial pathologies. Here, single- and multi-target ligand design was investigated to discover novel compounds active at multiple proteins/multiple binding sites including allosteric ligands. Calpain-1, a challenging target, was selected to develop and evaluate computational approaches to the discovery of novel ligands. Current selective calpain-1 inhibitors are reported to bind to an allosteric site and their mode of action has remained elusive. To elucidate this, a structure-based virtual screening protocol was implemented to find chemically novel compounds with improved selectivity and a reduced side-effects profile. To develop methods for the discovery of multi-target ligands, a multi-target design approach, which could be beneficial in the treatment of Lung Carcinoma and Neurodegenerative diseases, was investigated. A novel ensemble of proteins was targeted to elevate intracellular cAMP, deemed to be beneficial in these diseases resulting in the discovery of ligands with high binding affinity at three targets, PDE10A, A1 and A2A receptors. In tandem, functional activity at the A2A receptor and PDE10A was investigated, resulting in the discovery of novel compounds, which exhibited anti-proliferative effects in lung carcinoma cell-lines correlating with the co-expression of the two targets and increased cAMP levels. Critically, the dynamics of one amino acid residue, Val84, was identified as a novel conformational descriptor of A2A receptor activation. Overall, novel single- and multi-target ligand design approaches are presented in this work, which could be applicable to a wide range of ligand design problems, across (multi-factorial) disease areas and target families. The findings may facilitate improved design of allosteric calpain-1 inhibitors using the PEF(S) domain, and encourage investigating the therapeutic benefits of dual ligands at the A2A receptor and PDE10A against lung cancer in vivo.IDB Cambridge International Scholarship and ERC Starting Grant (No. 336159

Beyond the Conventional Quark Model: Using QCD Sum Rules to Explore the Spectrum of Exotic Hadrons

Exotic hadrons are theoretical structures allowed by our current understanding of Quantum Chromodynamics (QCD), lying outside the traditional $q\bar{q}$, $qqq$, or $\bar{q}\bar{q}\bar{q}$ understanding of mesons and baryons. These exotic hadrons potentially give us a unique window into the properties of the gluon, the nature of color confinement, and the strong interaction. As we progress through the precision-era of particle physics and experiments such as BESIII, Belle, BaBar, LHCb, GlueX, and PANDA amass experimental data across the expected mass ranges of exotic hadrons (such as hybrid mesons with both $\bar{q}q$ quark content and a gluonic component), theoretical predictions of the individual mass states and the overall multiplet structure are crucial in identifying exotic states as well as departures from predicted behaviour. Using the methodology of QCD sum-rules (QCDSRs), we explore the properties of exotic hadrons, and discuss the QCDSR methodology and its extensions

THE BALANCE BETWEEN DIPOLE-DIPOLE INTERACTIONS AND STERIC EXCLUSION ON ORDERING IN CATIONIC POLYMERS

Structure-property correlations in charged polymers is an interesting facet of polymer science. Understanding the effects of intermolecular forces on the morphologies of polymers can lead to the design of membranes with desired structures to improve properties, for example ion conductivity. In random, comb-shaped polycations, competing intermolecular forces result in two different short-range orderings. Side-chain steric repulsion results in backbone-backbone morphology characterized by periodic spacing between polymer backbones. However, dipole - dipole attraction in these polycations can facilitate the formation of ionomer cluster morphology characterized by a spacing between clustered dipoles. Although both of these short-range orderings have disparate origins, their similar dimensions when characterized by X-ray scattering can lead to a misattribution of one morphology for the other. To investigate this interplay between side-chain sterics and dipole-dipole attraction in polycations, random copolymers, and terpolymer of poly(4-vinylpyridine) (P4VP), polyisoprene (PI), and polystyrene (PS) were synthesized and fully quaternized with 1-alkylhalides. X-ray scattering show that in samples having 2 carbons on its pendant side-chain dipole-dipole attraction facilitates the formation of ionomer cluster morphology. Whereas samples with 4, or more carbons, on their pendant side-chains were dominated by side-chain sterics resulting in backbone-backbone morphology. Copolymers with polyisoprene, having flexible backbones, favored the formation of ionomer cluster morphology. An “In-Line” Dipole Model was developed to predict the separation between polymer backbones at which both ionomer cluster and backbone-backbone morphologies could coexist. The pendant polyisoprene units in the random copolymers of the fully quaternized P4VP and PI were crosslinked into robust anion exchange membranes (AEMs). Ionic conductivities for AEMs with coexistent morphologies were exceptionally high. To utilize these highly conducting AEM morphologies for fuel cell applications, stable quaternary ammonium monomers were designed, synthesized, and characterized. The monomers, norbonenepropoxy-6-azonia-spiro(5,5)undecane, and norbonenehexoxy-6-azonia-spiro(5,5)undecane, were readily polymerized into solvent processable AEMs. Random and block copolymerization of the stable quaternary ammonium monomers with norbornenemethylbenzylether were performed. The resultant copolymers were solvent processed into flexible anion conducting membranes. In the random copolymers, the competition between electrostatics and sterics facilitated the formation of coexistent morphologies resulting in high ionic conductivities in these membranes. In the block copolymers, electrostatics facilitated the formation of a continuous ionic phase even at low ionic volume fractions. This percolated phase in the block copolymers resulted in excellent bromide conductivity

Characterisation of the major porins OmpU and OmpT of Vibrio cholerae

PhD ThesisThe asymmetric outer membrane (OM) of a Gram-negative bacterium has many proteins embedded as β-barrel structures in it called outer membrane proteins (OMPs). The majority of these OMPs (porins) form non-selective channels across the OM to allow passive uptake of substrates. The treatment for infections caused by such bacteria mostly involves the administration of drugs/antibiotics, for which these porins play a very crucial role by providing an efficient (although not yet fully understood) route through their channel. The goal of this study is to study small-molecule permeation through the major porins, OmpU and OmpT, of Vibrio cholerae (the causative agent of cholera) for potential use of these proteins as the target for designing antibiotics or vaccines. Towards this project, we have succeeded in solving the 3D X-ray crystal structures of OmpU and OmpT as well as the structures of the major porins from Klebsiella pneumoniae (OmpK36) and Enterobacter cloacae (OmpE36, OmpE35). The proteins (OmpU/T, OmpE35/E36 and OmpK36) show the typical arrangement of porins with three β-barrel monomers arranged into a trimer. Each monomer displays 16 antiparallel β-strands forming the hollow β-barrel formed by 8 long extracellular loops and 8 short periplasmic turns. The latching loop L2 stabilises the trimer while loop L3 departs from the β-barrel fold and constricts the pore half-way through the channel. An unusual feature is observed in the channels of OmpU and OmpT that distinguishes them from other typical porins. In OmpU, the first 10 residues of N-terminus insert into the barrel and constrict the pore. In contrast, the structure of OmpT reveals that the extracellular loop L8 folds inwards to constrict the lumen of the channel. Such constriction elements not only reduce the pore sizes of OmpU and OmpT but may also dramatically affect the internal electrostatics of these channels, which is very important for small-molecule permeation. In addition, we also performed single channel electrophysiology experiments with OmpU and OmpT which revealed interesting features with the addition of carbapenems.European Union’s Seventh Framework Programme (FP7/2007–2013) and European Federation of Pharmaceutical Industries and Associations companies in kind contribution. Therefore, a very special gratitude goes out to all down to EU Marie Curie network (ITN) for funding my PhD

NASA patent abstracts bibliography: A continuing bibliography. Section 1: Abstracts (supplement 26)

Abstracts are provided for 172 patents and patent applications entered into the NASA scientific and technical information system during the period July 1984 through December 1984. Each entry consists of a citation, an abstract, and in most cases, a key illustration selected from the patent or patent application

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multi- target-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1- yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 μM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 μM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.The authors gratefully acknowledge the following financial supports: the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; European Regional Development Funds (grants RTI2018-093955-B-C21, SAF2015-64948-C2-1-R, and PID2021-122650OB-I00 to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L.); Spanish Na- tional Research Council (CSIC grants, PIE-202080E118 to M.I.R.-F. and PIE-202080I026 to R.L.); Health Institute Carlos III (grant PI17/01700 to R.L.); and General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827- NRF24ADCM). They thank the Ministry of Education of Spain for the following fellowships: FPU16/01704 and mobility grant FPUEST17/00233 (to C.H.-A.), FPU15/ 03269 (to C.F.-M.), FPU18/00630 (to E.d.S.), and FPU13/ 03737 (to P.M.). R.L. and M.G.L. also thank “Fundación Teófilo Hernando” for its continued support. The Spanish Medicinal Chemistry Society (SEQT) awarded the “Lilly Prize for Young Researchers” to this work, presented by C.H.-A. at the XIX SEQT Awards.Peer reviewe

Electrophysiological study of the somatic muscle cells of ascaris suum

The electrophysiological properties of muscle cells in the nematode Ascaris suum have been studied extensively (review DeBell 1965). However, details of the ionic mechanisms regulating the spontaneous activity of the somatic muscle cell membrane are still poorly understood. The study described in this thesis, used the patch-clamp technique to examine ion channels in the soma membrane of the muscle cells. In addition, two-electrode voltage-clamp was used to observe the membrane currents of the muscle cell somata.The patch-clamp experiments demonstrated the presence of a high-conductance chloride channel (200pS) spontaneously active at the resting potential. This channel was voltage sensitive. When the patch was depolarized the mean open time of the channel and the probability of opening were both reduced. An additional feature of this voltage sensitivity was the appearance of sub-conductance levels when the patch was depolarized.In patches that contained more than one channel the proportion of time spent with 1,2,3...N channels open was analysed in terms of the binominal distribution. The results indicated that the binomial distribution was not a good approximation to the data. From this analysis it was concluded that either the channels in the same patch did not have the same probability of opening, or that channel openings were not independent of each other.Experiments showed that the probability of chloride channel opening was dependent on the concentration of intracellular calcium. Increasing the concentration of calcium led to an increase in the probability of channel opening. The significance of the calcium sensitivity remains unknown. It was proposed that these channels were responsible for the high resting permeability to chloride.The voltage-clamp experiments demonstrated the presence of two currents activated by membrane depolarization. When the muscle cells were bathed in Ringers containing calcium, depolarization activated an inward current, followed by a large outward current. The inward current increased in amplitude when the calciun concentration of the bathing solution was increased, and was blocked by lanthanizn. The outward current was activated by steps to +55 mV from a holding potential of -35 mV. This current had a steep rise and slow decay and was found to be carried by potassium ions. Depolarizing steps of increased amplitude, increased the outward current amplitude and decreased the time to peak of the current. Experiments were carried out to determine the kinetics of the outward current.Two blockers of potassiun currents were tried in Ascaris, these were TEA and 4-AP. TEA [69 mM] was used in the study of the inward current and blocked most of the outward current. Bath application of 4-AP [5 mM] blocked a fast-transient component of the outward current. The current remaining after 4-AP application had a slow rise time, and a slow decay approximated by a single exponential, with a time constant of 1.1 s. The 4-AP resistant current shewed less steady-state inactivation than the gross outward current. Computer analysis was used to subtract the 4-AP resistant outward current from the gross outward current. The subtracted current represented the current blocked by 4-AP. The decay of the 4-AP blocked current was approximated by a single exponential, with a time constant of 10.4 ms. The function of both of these potassium conductances was thought to be to repolarize the cell after a spike