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Ligand Design

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https://read.qxmd.com/read/30878891/design-synthesis-and-dna-interaction-studies-of-furo-imidazo-3-3-3-propellane-derivatives-potential-anticancer-agents
#1
Alaa A Hassan, Ashraf A Aly, Nasr K Mohamed, Kamal M El Shaieb, Maysa M Makhlouf, El-Shimaa M N Abdelhafez, Stefan Bräse, Martin Nieger, Kevin N Dalby, Tamer S Kaoud
A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The aim of this study was to design and synthesize propellane derivatives that can act as DNA intercalators and/or groove binders. The unique structure of the propellane derivatives and their ability to display planar ligands with numerous possible geometries, renders them potential starting points to design new drugs targeting DNA in cancer cells...
February 13, 2019: Bioorganic Chemistry
https://read.qxmd.com/read/30878596/simultaneous-blocking-of-cd47-and-pd-l1-increases-innate-and-adaptive-cancer-immune-responses-and-cytokine-release
#2
Shu Lian, Ruizhi Xie, Yuying Ye, Xiaodong Xie, Shuhui Li, Yusheng Lu, Bifei Li, Yunlong Cheng, Vladimir L Katanaev, Lee Jia
BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response. METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance...
March 14, 2019: EBioMedicine
https://read.qxmd.com/read/30878562/crystallographic-screening-using-ultra-low-molecular-weight-ligands-to-guide-drug-design
#3
Marc O'Reilly, Anne Cleasby, Thomas G Davies, Richard J Hall, R Frederick Ludlow, Christopher W Murray, Dominic Tisi, Harren Jhoti
We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5-7) to identify ligand-binding hot and warm spots on proteins. We propose that MiniFrag screening represents a highly effective method for guiding optimisation of fragment-derived lead compounds or chemical tools and that the high screening hit rates reflect enhanced sampling of chemical space.
March 13, 2019: Drug Discovery Today
https://read.qxmd.com/read/30877995/promoting-solar-to-hydrogen-evolution-on-schottky-interface-with-mesoporous-tio-2-cu-hybrid-nanostructures
#4
Jiaxin Zhu, Jinyan Xiong, Gang Cheng, Weijie Li, Shixue Dou
Developing a highly efficient photocatalysis system based on a photocatalyst-cocatalyst host for the hydrogen evolution reaction has potential but is still challenging. Herein, we report enhanced splitting of water achieved by loading copper metal particles on mesoporous TiO2 microrods through involving of dual ligand agents into the reaction system. The composition, structure, and surface characteristics of the TiO2 -Cu hybrid were analyzed by X-ray diffraction, X-ray photoelectron spectroscopy, scanning and transmission electron microscopy, and nitrogen adsorption...
March 6, 2019: Journal of Colloid and Interface Science
https://read.qxmd.com/read/30877895/modulating-the-antitumoral-activity-by-the-design-of-new-platinum-ii-compounds-synthesis-characterization-dft-ultrastructure-and-mechanistic-studies
#5
Rafaela O Moreira, Samila R Morcelli, Milton M Kanashiro, Jackson A L C Resende, Leide L F Maciel, João Carlos de A Almeida, Lawrence R Gahan, Adolfo Horn, Christiane Fernandes
The synthesis, physico-chemical characterization, Density functional theory (DFT) calculation and cytotoxicity against five human tumoral cell lines (THP-1, U937, Molt-4, Colo205 and H460) of four new platinum(II) coordination compounds are reported, i.e. [Pt(HL1)Cl]·H2 O (1), [Pt(HL2)Cl]·H2 O (2), [Pt(HL3)Cl]·H2 O (3) and [Pt(HL4)Cl]·H2 O (4). The ligands contain N2O donor sets. Furthermore, H2L3 and H2L4 present α and β-naphthyl groups respectively, which are absent in HL1 and H2L2. X-ray diffraction studies were performed for complex (3), indicating the formation of a mononuclear platinum(II) complex...
January 30, 2019: Journal of Inorganic Biochemistry
https://read.qxmd.com/read/30877540/neonicotinoid-insecticide-design-molecular-docking-multiple-chemometric-approaches-and-toxicity-relationship-with-cowpea-aphids
#6
Alina Bora, Takahiro Suzuki, Simona Funar-Timofei
Neonicotinoids are the fastest-growing class of insecticides successfully applied in plant protection, human and animal health care. The significant resistance increases led to the urgent need for alternative new neonicotinoids, with improved insecticidal activity. We performed molecular docking to describe a common binding mode of neonicotinoids into the nicotinic acetylcholine receptor, and to select the appropriate conformations to derive models. These were further used in a QSAR study employing both linear and nonlinear approaches to model the inhibitory activity against the Cowpea aphids...
March 14, 2019: Environmental Science and Pollution Research International
https://read.qxmd.com/read/30875980/modulation-of-disordered-proteins-with-a-focus-on-neurodegenerative-diseases-and-other-pathologies
#7
REVIEW
Anne H S Martinelli, Fernanda C Lopes, Elisa B O John, Célia R Carlini, Rodrigo Ligabue-Braun
Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer's, Parkinson's, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety...
March 15, 2019: International Journal of Molecular Sciences
https://read.qxmd.com/read/30875739/killing-mechanisms-of-chimeric-antigen-receptor-car-t-cells
#8
REVIEW
Mohamed-Reda Benmebarek, Clara Helke Karches, Bruno Loureiro Cadilha, Stefanie Lesch, Stefan Endres, Sebastian Kobold
Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma...
March 14, 2019: International Journal of Molecular Sciences
https://read.qxmd.com/read/30875506/modeling-caspase-1-inhibition-implications-for-catalytic-mechanism-and-drug-design
#9
Carlos A Ramos-Guzmán, Kirill Zinovjev, Iñaki Tuñón
The metabolic product of caspase-1, IL-1β, is an important mediator in inflammation and pyroptosis cell death process. Alzheimer's disease, septic shock and rheumatoid arthritis are IL-1β mediated diseases, making the caspase-1 an interesting target of pharmacological value. Many inhibitors have been developed until now, most of them are peptidomimetic with improved potency. In the present study, all-atom molecular dynamics simulations and the MM/GBSA method were employed to reproduce and interpret the results obtained by in vitro experiments for a series of inhibitors...
February 27, 2019: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/30874276/conjugated-rigidified-bibenzimidazole-ancillary-ligands-for-enhanced-photoluminescence-quantum-yields-of-orange-red-emitting-iridium-iii-complexes
#10
Adam F Henwood, Daniel Antón-García, Mégane Morin, Diego Rota Martir, David B Cordes, Colin Casey, Alexandra M Z Slawin, Tomas Lebl, Michael Bühl, Eli Zysman-Colman
A series of six novel [Ir(C^N)2(N^N)](PF6) complexes (C^N is one of two cyclometalating ligands: 2-phenyl-4-(2,4,6-trimethylphenyl)pyridine, MesppyH, or 2-(napthalen-1-yl)-4-(2,4,6-trimethylphenyl)pyridine, MesnpyH; N^N denotes one of four neutral diamine ligands: 4,4'-di-tert-butyl-2,2'-bipyridine, dtbubpy, 1H,1'H-2,2'-bibenzimiazole, H2bibenz, 1,1'-(α,α'-o-xylylene)-2,2'-bibenzimidazole, o-xylbibenz or 2,2'-biquinoline, biq) were synthesised and their structural, electrochemical and photophysical properties comprehensively characterised...
March 15, 2019: Dalton Transactions: An International Journal of Inorganic Chemistry
https://read.qxmd.com/read/30873002/an-intersectional-approach-to-target-neural-circuits-with-cell-and-projection-type-specificity-validation-in-the-mesolimbic-dopamine-system
#11
Nefeli Kakava-Georgiadou, Maria M Zwartkruis, Clara Bullich-Vilarrubias, Mieneke C M Luijendijk, Keith M Garner, Geoffrey van der Plasse, Roger A H Adan
Development of tools to manipulate activity of specific neurons is important for dissecting the function of neural circuits. Viral vectors and conditional transgenic animal lines that target recombinases to specific cells facilitate the successful manipulation and recording of specific subsets of neurons. So far, it has been possible to target neuronal subtypes within a certain brain region based on transcriptional control regions from a gene selectively expressed in those cells or based upon its projections...
2019: Frontiers in Molecular Neuroscience
https://read.qxmd.com/read/30872479/molecular-dynamics-guided-discovery-of-an-ago-allosteric-modulator-for-gpr40-ffar1
#12
Michael Lückmann, Mette Trauelsen, Marie A Bentsen, Tinne A D Nissen, Joao Martins, Zohreh Fallah, Mads M Nygaard, Elena Papaleo, Kresten Lindorff-Larsen, Thue W Schwartz, Thomas M Frimurer
The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII...
March 14, 2019: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30872157/modulation-of-protein-oligomerization-an-overview
#13
REVIEW
Neha Kumari, Savita Yadav
A large section of cellular proteins in both prokaryotic and eukaryotic systems have oligomeric property. Intently, oligomerization of protein is an invaluable phenomenon from the point of view of protein evolution. This review comprises an overview on modulation of protein oligomerization. The comprehensive modulation of protein oligomerization can be supportive for effective drug designing in future. Most common mechanisms of protein oligomerization are domain swapping and ligand induced dimerization. Infrequent mechanism of protein oligomerization involves point mutations at dimer interface, post-translational modification and insertion/deletion at interface...
March 11, 2019: Progress in Biophysics and Molecular Biology
https://read.qxmd.com/read/30871220/binding-of-braco19-to-a-telomeric-g-quadruplex-dna-probed-by-all-atom-molecular-dynamics-simulations-with-explicit-solvent
#14
Babitha Machireddy, Holli-Joi Sullivan, Chun Wu
Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid)...
March 13, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/30870571/doubt-on-a-dogma-aquation-of-equatorial-ligands-of-pt-iv-complexes-under-physiological-conditions
#15
Alexander Kastner, Isabella Poetsch, Josef Mayr, Jaroslav V Burda, Alexander Roller, Petra Heffeter, Bernhard K Keppler, Christian R Kowol
Due to their higher kinetic inertness and consequently reduced side reactions with biomolecules, Pt(IV) complexes are considered as the future of anticancer platinum drugs. We investigated the aqueous stability of a series of biscarboxylato Pt(IV) complexes under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes revealed fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the formed hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for activation of Pt(IV) drugs also changing the anticancer potential of the compounds in cell culture...
March 14, 2019: Angewandte Chemie
https://read.qxmd.com/read/30869724/mononuclear-lanthanide-complexes-assembled-from-a-tridentate-nno-donor-ligand-design-of-a-dy-iii-single-ion-magnet
#16
Pankaj Kalita, Amit Malakar, Joydeb Goura, Subhashree Nayak, Juan Manuel Herrera, Enrique Colacio, Vadapalli Chandrasekhar
The reaction of a tridentate NNO donor ligand, 4-nitro-2-((2-(pyridine-2-yl)hydrazono)methyl)phenol (HL) with lanthanide(iii) nitrates in the presence of triethylamine afforded a new family of neutral mononuclear LnIII complexes [Ln(NO3)(L)2(HOCH3)] (Ln = Gd; (1) Tb; (2), Dy; (3), and Ho (4). The mononuclear complexes were structurally characterized by single crystal X-ray diffraction studies which revealed a spherical tricapped trigonal prism geometry with a pseudo D3h symmetry around the LnIII centre. Static (dc) and dynamic (ac) magnetic studies have been performed on these complexes...
March 14, 2019: Dalton Transactions: An International Journal of Inorganic Chemistry
https://read.qxmd.com/read/30869695/an-unprecedented-hetero-bimetallic-three-dimensional-spin-crossover-coordination-polymer-based-on-the-tetrahedral-hg-secn-4-2-building-block
#17
Wenlong Lan, Francisco Javier Valverde-Muñoz, Xiaoyun Hao, Yong Dou, M Carmen Muñoz, Zhen Zhou, Hui Liu, Qingyun Liu, José Antonio Real, Daopeng Zhang
Self-assembly of octahedral FeII ions, trans-1,2-bis(4-pyridyl)ethane (bpe) bridging ligands and [Hg(XCN)4]2- (X = S (1), Se (2)) tetrahedral building blocks has afforded a new type of hetero-bimetallic HgII-FeII spin-crossover (SCO) 3D 6,4-connected coordination polymer (CP) formulated {Fe(bpe)[Hg(XCN)4]}n. For X = S (1), the ligand field is close to the crossing point but 1 remains paramagnetic over all temperatures. In contrast, for X = Se (2) the complex undergoes complete thermal induced SCO behaviour centred at T1/2 = 107...
March 14, 2019: Chemical Communications: Chem Comm
https://read.qxmd.com/read/30869664/bifunctional-magnetopolymersomes-of-iron-oxide-nanoparticles-and-carboxymethylcellulose-conjugated-with-doxorubicin-for-hyperthermo-chemotherapy-of-brain-cancer-cells
#18
Sandhra M Carvalho, Alice G Leonel, Alexandra A P Mansur, Isadora C Carvalho, Klaus Krambrock, Herman S Mansur
Glioblastoma is the most aggressive primary brain cancer, which has no cure yet. Emerging nanotheranostic alternatives such as magnetic iron oxide nanoparticles (MIONs) have great potential as multimodal cancer therapy mediators. They can act as nanocarriers of anticancer drugs and generate localized heat when exposed to an alternating magnetic field (AMF), resulting in combined effects of chemotherapy and magnetic hyperthermia therapy. Thus, we designed and synthesized novel MIONs directly through a co-precipitation method by a single step one-pot aqueous green process using carboxymethylcellulose (CMC) as a multifunctional, biocompatible and water-soluble biopolymer ligand (iron oxide nanoparticle-CMC, MION@CMC)...
March 14, 2019: Biomaterials Science
https://read.qxmd.com/read/30869514/selective-separation-and-complexation-of-trivalent-actinide-and-lanthanide-by-a-tetradentate-soft-hard-donor-ligand-solvent-extraction-spectroscopy-and-dft-calculations
#19
Lei Xu, Ning Pu, Youzhen Li, Pingping Wei, Taoxiang Sun, Chengliang Xiao, Jing Chen, Chao Xu
Recently, phenanthroline-based ligands have received increasing attention due to their excellent separation capabilities for trivalent actinides over lanthanide. In this work, we designed a soft-hard donor combined tetradentate phenanthroline-based extractant, tetraethyl (1,10-phenanthrolin-2,9-diyl)phosphonate (C2-POPhen), for the selective separation of trivalent Am(III) over Ln(III) from HNO3 media. The solvent extraction and complexation behaviors of Am(III) and Ln(III) by C2-POPhen were investigated both experimentally and theoretically...
March 14, 2019: Inorganic Chemistry
https://read.qxmd.com/read/30868880/systematic-mapping-of-binary-nanocrystal-superlattices-the-role-of-topology-in-phase-selection
#20
Igor Coropceanu, Michael A Boles, Dmitri V Talapin
The self-assembly of two sizes of spherical nanocrystals has revealed a surprisingly diverse library of structures. To date at least fifteen distinct binary nanocrystal superlattice (BNSL) structures have been identified. The stability of these binary phases cannot be fully explained using the traditional conceptual framework treating the assembly process as entropy-driven crystallization of rigid spherical particles. Such deviation from hard sphere behavior may be explained by the soft and deformable layer of ligands that envelops the nanocrystals, which contributes significantly to the overall size and shape of assembling particles...
March 14, 2019: Journal of the American Chemical Society
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