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ABSTRACT Copolymerization behavior of ethylene (E) and propylene (P) using ansa-dimethylsilylene(fluorenyl)(amido)dimethyltitanium complex was investigated. P was more reactive than E regardless of the chain-end monomer unit, which was very unusual in the coordination polymerization system. The terpolymerizations of E, P and norbornene (NB) or 5-ethylidene-2-norbornene (5E2N) were also performed. The each content in the E/P/NB terpolymer was independently controlled by the initial concentration of NB and E/P feed ratio. Glass transition temperature ( Tg) of the terpolymer was raised in proportion to the NB content and close to that of the corresponding NB/E random copolymer with the same NB content. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 685-691 [ABSTRACT FROM AUTHOR]

ABSTRACT This article reports the synthesis and the properties of novel thermoplastic elastomers of A-B-A type triblock copolymer structure, where the hard segment A is poly( l-lactide) (PLLA) and the soft segment B is poly( ε-caprolactone- stat- d, l-lactide) (P(CL- stat-DLLA)). The P(CL- stat-DLLA) block with DLLA content of 30 mol % was applied because of its amorphous nature and low glass transition temperature ( Tg = approximately −40 °C). Successive polymerization of l-lactide afforded PLLA- block-P(CL- stat-DLLA)- block-PLLAs, which exhibited melting temperature ( Tm = approximately 150 °C) for the crystalline PLLA segments and still low Tg (approximately −30 °C) of the soft segments. The triblock copolymers showed very high elongation at break up to approximately 2800% and elastic properties. The corresponding d-triblock copolymers, PDLA- block-P(CL- stat-DLLA)- block-PDLAs (PDLA = poly( d-lactide)) were also prepared with the same procedure using d-lactide in place of l-lactide. When the PLLA- block-P(CL- stat-DLLA)- block-PLLA was blended with PDLA- block-P(CL- stat-DLLA)- block-PDLA, stereocomplex crystals were formed to enhance their Tm as well as tensile properties. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 489-495 [ABSTRACT FROM AUTHOR]

Synthesis of a multiblock copolymer composed of cis-1,4-polybutadiene (PBd) segments and poly(3-buten-1-ol) segments is performed via successive hydroboration and oxidation of cis-1,4/ syn-1,2-multiblock PBd. The ratio of functionalization can be controlled by changing the amount of the borane reagent. The obtained polymer shows two distinctive glass-transition temperatures, which correspond to the cis-1,4-PBd block and the poly(3-buten-1-ol) block. These thermal properties clearly show that the functionalization of the PBd proceeds keeping the elastic property derived from cis-1,4 segment. [ABSTRACT FROM AUTHOR]

ABSTRACT A-B-A block copolymers which consist of poly(norbornene- co-1-octene) and atactic polypropylene (PP) segments were synthesized by using ansa-fluorenylamidotitanium complex as a catalyst varying the ratio of norbornene, 1-octene, and propylene. The copolymer was obtained quantitatively with high molecular weight (>100,000) and narrow molecular weight distribution (polydispersity index, <1.5). A-B block copolymers of poly(norbornene- co-1-octene) and poly(methyl methacrylate) (PMMA) was also obtained by the same procedure. Mechanical and optical properties of these copolymer films, which were obtained by solution casting process, were also investigated. Introduction of PP soft segment greatly improved mechanical properties, keeping their high transparency. Introduction of PMMA block also increased the tensile strength. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 267-271 [ABSTRACT FROM AUTHOR]

ansa-Dimethylsilylene(fluorenyl)( t-butylamido)dimethyltitanium complex, Me2Si( η3-C13H8)( η1-N tBu)TiMe2 (1 ), and its tetraalkylsubsutituted-fluorenyl derivative, Me2Si( η3-C29H36)( η1-N tBu)TiMe2 (2), are used as catalysts for ethylene/1-hexene copolymerization activated by modified methylalminoxane. 2 is found to show remarkable activity and affords high-molecular-weight polymer compared with 1. The monomer reactivity ratios, rE and rH, are determined to be rE = 3.0 ± 0.15, rH = 0.19 ± 0.06 for 1, and rE = 2.9 ± 0.15, rH = 0.27 ± 0.02 for 2, indicating that 2 incorporates 1-hexene slightly more than 1. [ABSTRACT FROM AUTHOR]

A series of titanium complexes with ansa-(fluorenyl)(cyclododecylamido) ligands, Me2Si(η3-R)(N- c-C12H23)TiMe2 [R = fluorenyl ( 5), 2,7- tBu2fluorenyl ( 6), 3,6- tBu2fluorenyl ( 7)], was synthesized. The crystal structure of complex 6 revealed η3-coordination of the fluorenyl moiety to the metal. Upon activation with trialkylaluminum-free modified methylaluminoxane, complexes 5- 7 as well as the corresponding tBu amide complexes, Me2Si(η3-R)(N tBu)TiMe2 [R = fluorenyl ( 2), 2,7- tBu2fluorenyl ( 3), 3,6- tBu2fluorenyl ( 4)], were adopted as the catalysts for the copolymerization of ethylene (E) and isobutylene (IB). Among these complexes, complex 6 was found to achieve the highest IB incorporation to produce alternating E-IB copolymers. Complex 6 system also achieved copolymerization of E and limonene. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013 [ABSTRACT FROM AUTHOR]

Chromium complexes with N, N, N-tridentate ligands, LCrCl (L = 2,6-bis{(4S)-(−)-isopropyl-2-oxazolin-2-yl}pyridine (), 2,2′:6′,2″-terpyridine (), and 4,4′,4″-tri- tert-butyl-2,2′:6′,2″-terpyridine ()), were prepared. The structures of and were determined by X-ray crystallography. Upon activation with modified methylaluminoxane (MMAO), catalyzed the polymerization of 1,3-butadiene, while and was inactive. The obtained poly(1,3-butadiene) obtained with -MMAO was found to have completely trans-1,4 structure. The -MMAO system also showed catalytic activity for the polymerization of isoprene to give polyisoprene with trans-1,4 (68%) and cis-1,4 (32%) structure. Copyright © 2011 Society of Chemical Industry Upon activation with modified methylaluminoxane (MMAO), the chromium complex CrCl[2,6-bis{(4 S)-(−)-isopro-pyl-2-oxazolin-2-yl}pyridine] () was found to polymerize 1,3-butadiene to produce completely trans-1,4-polymer. [ABSTRACT FROM AUTHOR]

This article reports the synthesis and characterization of an extremely high thermostable cyclic olefin copolymer with advanced optical properties resulting from the vinyl addition copolymerization of norbornene with styrene catalyzed by a substituted fluorenylamidodimethyltitanium catalyst [Me2Si(3,6- tBu2Flu)( tBuN)]TiMe2 activated with a [Ph3C] [B(C6F5)4]/Al( iBu)3 cocatalyst using o-dichlorobenzene as solvent. The prepared copolymer possesses a glass transition temperature as high as polyimide ( Tg > 300 °C) and a high transmittance which is comparable with that of the conventional optical resins ([T] > 90%). The incorporation of polystyrene, which exhibits a negative birefringence into the vinyl-added polynorbornene that possesses an intrinsic positive birefringence, effectively reduced the birefringent magnitude of the norbornene-styrene copolymer due to a mutual compensation between these opposite-sign birefringences. The absence of any functional and aromatic heterocyclic groups and the presence of highly hydrophobic saturated bicyclic rings in the copolymer main chains effectively prevented the diffusion of water/oxygen and thus enhanced the dimensional and optical stabilities of the material. Preliminary results on the characterization of the thermal stability, mechanical, and optical properties of the vinyl-added norbornene-styrene copolymers indicate that they satisfy all the rigorous requirements for a polymer to be applied as a flexible substrate for the manufacturing of the flexible displays. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010 [ABSTRACT FROM AUTHOR]

ansa -Fluorenylamidotitanium complexes bearing various substituents on the nitrogen and fluorene ( 2a-d ) were synthesized. The structures of the complexes were characterized by 1 H and 13 C NMR, and X-ray crystal analyses were performed for complexes 2a , 2b and 2d . The coordination mode of the fluorenyl group to the metal center was changed from η 3 to η 1 when a bulky group was introduced on the nitrogen or 2,3-position of the fluorenyl ring. Syndiotactic-specificity of the catalyst for the propylene polymerization was reduced when bulky group was introduced on the nitrogen. Least-square fitting analysis of the steric pentad distributions revealed that the stereodefect was mainly formed by the chain migration without monomer insertion, which is accelerated by the η 1 -coordination of the fluorenyl group. [ABSTRACT FROM AUTHOR]

Polypropylene (PP) membrane with low porosity and poor hydrophilicity limits the performance of lithium-ion batteries. In mechanism, the function of amorphous structure of precursor film on microporous structure of PP membrane is yet unknown. In this work, the porous and hydrophilic PP/reduced hydroxyl-modified polypropylene (PPrOH) membrane was fabricated by blending esterified-PPOH firstly and then hydrolyzing to introduce the hydrogen bond in amorphous region and avoid phase separation. The results showed that the hydrogen bond was successfully introduced into the amorphous region of PP/PPrOH film and led to an increase of physical crosslinking points. Therefore, a large region of microphase separation emerged in the PP/PPrOH membrane after cold stretching, which resulted in a 45.6 % increase of porosity at maximum compared to the PP membrane. Besides, the hydrophilicity of PP/PPrOH membrane was improved with the blend content exceeding 10 wt%. Eventually, the lithium-ion conductivity of PP/PPrOH-10 membrane enhanced by 37.5 % over the base PP membrane. This work provides a novel perspective for preparing hydrophilic PP membrane with high porosity. [Display omitted] • Introducing hydrogen bond in amorphous of PP film by melt blending with PPrOH. • Hydrogen crosslinking in amorphous results in more region of microphase separation at stretching. • Addition of PPrOH increases porosity by 45.6 % and enhances lithium-ion conductivity by 37.5 % compared to PP membrane. • Crosslinking density in amorphous is positively correlated with porosity of membrane. [ABSTRACT FROM AUTHOR]

Me2Si(C29H36)(N tBu)TiMe2 ( 4; C29H36, octamethyloctahydrodibenzofluorenyl) was synthesized and characterized by elemental analysis, 1H NMR and single crystal X-ray analysis. The complex was applied for propene polymerization using dried modified methylaluminoxane (dMMAO) as a cocatalyst at 0 °C by a semi-batch method. The catalytic system showed the activity of 11,400 kg-polymer mol-Ti−1 h−1, which was too high to control the polymerization. Batch-wise polymerizations were then conducted by changing the amount of propene in feed. The polymerizations proceeded quantitatively, and the number-average molecular weight increased linearly against the polymer yield with keeping the number of polymer chains constant although the polydispersity indices were broader than that expected in a living polymerization. The results of postpolymerization indicated the smooth chain transfer after the monomer consumption. [ABSTRACT FROM AUTHOR]

The practical synthesis of polar‐functionalized polyolefins using transition‐metal‐catalyzed copolymerization of olefins with polar monomers is a challenge; the use of heterogeneous catalysts is little explored. Herein, we report the synthesis of heterogeneous naphthoquinone‐based nickel (Ni/SiO2) and palladium (Pd/SiO2) catalysts through hydrogen bonding interactions of the ligands with the silica surface. Ni/SiO2 exhibits high activities (up to 2.65×106 g mol−1 h−1) during the copolymerization of ethylene with 5‐hexene‐1‐yl‐acetate, affording high‐molecular‐weight (Mn up to 630 000) polar‐functionalized semicrystalline polyethylene (comonomer incorporation up to 2.8 mol %), along with great morphology control. The resulting copolymers possess improved surface properties and great mechanical properties. Pd/SiO2 can mediate ethylene copolymerization with polar monomers with moderate activity to produce high‐molecular‐weight copolymers with tunable comonomer incorporation. [ABSTRACT FROM AUTHOR]

• A series of novel N -acylated imidazolin-2-imine neutral nickel complexes are synthesized. • High catalytic activity and tolerability toward polar comonomer is achieved. • Rational ligand design by tuning the electronic effects around metal center is important. By taking advantage of electronic influence of ligand design, the novel neutral nickel complexes bearing strong electron-donating N -acylated imidazolin-2-imine ligand were synthesized and characterized. The nickel catalysts conducted ethylene polymerization with high activity and good thermal stability, affording semicrystalline polyethylene with short chain branches (32–46/1000 C atoms). The complex Ni2 bearing adamantyl substituent on the imidazoline ligand showed higher activity than phenyl substituted complex Ni1 , and highest activity was observed at 60 °C (up to ~106 g⋅mol−1⋅h−1). Most importantly, the catalysts were also effective for the copolymerization of ethylene and 5-hexenyl acetate with moderate activity (~105 g⋅mol−1⋅h−1). The microstructure analyses by the 13C NMR spectroscopy indicated that the 5-hexenyl acetate was successfully incorporated into the polyethylene main chain with reasonable comonomer content. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • High-performance nickel catalysts bearing an anilinoanthraquinone ligand, which can be obtained with straightforward synthetic route, were developed for the ethylene copolymerization and norbornene copolymerization with polar monomers. • The dinuclear nickel catalysts exhibit higher activity and polar monomer incorporation than corresponding mononuclear analogue. Abstract The introduction of even low amount of polar functional group is important to expand the range of polyolefin properties. The palladium-catalyzed copolymerization of olefins with polar monomers is a valuable method for the direct synthesis of polar functionalized polyolefins, while low-cost nickel-based catalysts for these copolymerizations still have been limited. Here we report a series of mono- and dinuclear nickel complexes based on structurally simple anilinoanthraquinone ligand for the ethylene copolymerization and norbornene copolymerization with polar monomers. The dinickel catalysts exhibit higher activity and polar monomer incorporation than corresponding mononuclear analogue, owing to the electronic cooperativity effects between the two nickel centers through conjugated ligand. [ABSTRACT FROM AUTHOR]

A series of higher 2-alkenes, i.e., 2 - pentene, 2 - hexene and 2 - octene were polymerized with phenyl substituted α- diimine nickel complexes in combination with modified methylaluminoxane (MMAO) to produce branched poly(2 - alkene)s with high molecular weight and narrow molecular weight distribution ( M w / M n < 1.8). At 0 °C, these 2 - alkenes polymerized in a living manner to produce amorphous polymers with glass transition temperature of – 70 ∼ – 65 °C. The microstructures of the produced polymers indicated the 2,3 - and 3,2 - insertion followed by chain - walking and the incorporation of a small amount of 1-alkene formed by isomerization. The branch structures were significantly depended on the polymerization temperature, and the ratio of methyl branch predominantly derived from 3,2 - insertion was increased with increasing the polymerization temperature. [ABSTRACT FROM AUTHOR]

Cyclic olefin copolymers (COCs), among which ethylene (E)/norbornene (NB) copolymer have been commercialized, are novel optical plastics but their brittleness narrows their application fields. In this research, star polymers with NB/1-octene (O) gradient copolymer arms and cross-linked cores were synthesized by adding norbornadiene (NBD)/E or 1,11-dodecadiene (DOD) after NB/O copolymerization using a ( t BuNSiMe 2 Flu)TiMe 2 (I)-[Ph 3 C][B(C 6 F 5) 4 ] catalyst system with 2,6-di- tert -butyl-4-methylphenol-treated tri- n -octylaluminum (Oct 3 Al/BHT) as a scavenger. The obtained star polymers possessed the O-rich soft segments close to the core and the NB-rich hard segments in the outer layer. The DOD-cored star polymers had a larger number of arms (15) and a higher star polymer content (68 wt%) than the NBD/E-cored ones (6 and 58 wt%, respectively). The films of the mixtures of the star and the corresponding arm polymers were molded by a melt-pressing procedure. The tensile properties of the films of the DOD-cored star polymer mixtures were significantly improved compared to those of the arm polymers. The Young's modulus, yield stress, strength, and strain at break were controlled by the NB content, the arm length, and the gradient structure of the arms. These results clarified the novelty of the star-shaped NB/ α -olefin copolymers and would expand the application fields of COCs. [Display omitted] • Star-shaped polymers with norbornene/1-octene gradient copolymer arms were synthesized by an "arm-first" strategy. • The star-shaped polymers showed two T g values assignable to an octene-rich soft core and a norbornene-rich hard sphere. • Transparent films were obtained from the blend of the star and the arm polymers by melt processing. • The of mechanical properties of the blend films were improved compared with those of the arm polymer films. • The thermal and the star polymers were controlled by the arm length and the norbornene content. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-[1-(2,6-dibenzhydryl-4-chlorophenylimino)ethyl]-6-[1-(arylimino)ethyl]pyridine ligands (L1–L5) as well as the ligand 2,6-bis[1-(2,6-dibenzhydryl-4-chloro-phenylimino)ethyl]pyridine (L6) were synthesized and reacted with FeCl2·4H2O to afford the iron(II) dichloride complexes [LFeCl2] (Fe1–Fe6). All new compounds were fully characterized by elemental and spectroscopic analysis, and the molecular structures of the complexes Fe1, Fe2 and Fe4 were determined by single-crystal X-ray diffraction, which revealed a pseudo-square-pyramidal geometry at iron. Upon activation with either MAO or MMAO, all iron pre-catalysts exhibited very high activity in ethylene polymerization with good thermal stability. To the best of our knowledge, the current system showed the highest activity amongst iron bis(imino)pyridine pre-catalysts reported to-date. The polymerization parameters were explored to determine the optimum conditions for catalytic activity, which were typically found to be 2500 eq. Al to Fe at 60 °C in the presence of MMAO, and 80 °C in the presence of MAO. The resultant polyethylene possessed a narrow molecular polydispersity index (PDI) consistent with the formation of single-site active species. [Copyright &y& Elsevier]

Abstract: Catalytic behavior of tetrahydroborate complexes of rare earth metals, Ln(BH4)3(THF) x (1: Ln=La, x =3; 2: Ln=Pr, x =2; 3: Ln=Nd, x =3; 4: Ln=Sm, x =3; 5: Ln=Y, x =2.5; 6: Ln=Yb, x =3), for ring-opening polymerization (ROP) of six-membered cyclic esters, δ-valerolactone (VL) and d,l-lactide (d,l-LA), was studied. The controlled polymerization of VL with 1–6 proceeded in THF at 60°C. The catalytic activities of these complexes for the ROP of VL were observed to be in order of the ionic radii of the metals: 1(La)≥ 2(Pr)≥ 3(Nd)> 4(Sm)> 5(Y)> 6(Yb). The obtained polymers were demonstrated to be hydroxy-telechelic by 1H NMR and MALDI-TOF MS spectroscopy. The controlled ROP of d,l-LA also proceeded by these complexes. The activities of these complexes for the d,l-LA ROP were also in order of the ionic radii of the metals. [Copyright &y& Elsevier]

[Display omitted] • A series of 1,2-bis(imidazolidin-2-imine)benzene nickel complexes are synthesized. • Copolymerization of norbornene and styrene is achieved with high activity. • The nickel catalyst exhibits good thermal stability to give functionalized COCs. A series of 1,2-bis(imidazolidin-2-imine)benzene nickel complexes with different substituents on the imidazolidin-2-imine or benzene ring was synthesized and characterized. The complexes exhibited a tetrahedral configuration, and Ni2 bearing a phenyl substituent on the imine ligand provided highest steric hinderance around nickel center with a buried volume percentage of 53.1%. The nickel complexes in the presence methylaluminoxane (MAO) were highly active for the addition polymerization of norbornene and exhibited good thermal stability, where Ni3 bearing fluorine substituent on the benzene ligand backbone showed highest activity of 1.68 × 106 g·mol−1·h−1 at 100 °C to produce high molecular weight polynorbornene (1.2 × 105 g·mol−1). Most importantly, the catalysts promoted the copolymerization of norbornene and styrene with high activity (～105 g·mol−1·h−1), high molecular weight (~104 g·mol−1), and tunable styrene content (up to 17 mol%) and glass transition temperature. The linear relationship between the glass transition temperature and styrene content indicated the formation of the uniform copolymers. A preference for the norbornene insertion in each catalytic system was investigated by the evaluation of the monomer reactivity ratios. [ABSTRACT FROM AUTHOR]

The development of a palladium catalyst that has enhanced catalytic performance, such as low aluminum cocatalyst loading, good copolymerization ability, high molecular weight, and excellent solubility of the (co)polymers, is still a challenge in norbornene copolymerizations. Here, a series of PdCl 2 and PdMeCl complexes containing differently substituted anilines and imidazolidin-2-imine/guanidine ligands was successfully synthesized and characterized. X-ray diffraction analysis results revealed that these Pd complexes adopted an almost square-planar geometry, and the six-membered chelate ring showed structural distinctions as compared to traditional N^N-based α-diimine and β-diimine Pd complexes. These Pd complexes were activated by EtAlCl 2 and then exhibited moderate activity (10 4 -10 5 g mol -1 h -1 ) and good thermal stability (up to 90 °C) for norbornene polymerization to produce high-molecular-weight PNBs ( M n up to 96.4 kg mol -1 ) with narrow polydispersities (PDI as low as 1.39). These Pd complexes also exhibited good polar group tolerance in the copolymerization of norbornene with methyl 5-norbornene-2-carboxylate and methyl 10-undecenoate, in which the activity was achieved up to 7.04 × 10 4 g mol -1 h -1 . It furnished polar functionalized norbornene-based copolymers with high molecular weight ( M n up to 63.1 kg mol -1 ), narrow PDI, reasonable polar monomer incorporation, and good solubility. These Pd catalysts exhibited an enhanced copolymerization ability to produce PNB or NB-based copolymers, representing significant progress in this field.

RNA molecules are essential for carrying genetic information and regulating gene expression in most organisms including human pathogenic RNA and relate retro viruses. Targeting viral RNA (vRNA) structures provide broad opportunities to develop chemical tools to probe molecular virology and to discover novel targets for therapeutic intervention. An increasing number of RNA binding small molecules are being identified, stimulating increased interests in small molecule drug discovery for RNA targets. In this chapter, we describe protocols to characterize and robustly validate vRNA-small molecule (vRNA-sm) interactions starting from vRNA sample preparation, followed by small molecule screening against vRNA targets and finally to validating the vRNA-sm interactions via NMR spectroscopy and calorimetric titrations., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The rapidly accelerating characterization of RNA tertiary structures has revealed their pervasiveness and active roles in human diseases. Small molecule-mediated modulation of RNA tertiary structures constitutes an attractive avenue for the development of tools for therapeutically targeting and/or uncovering the pathways associated with these RNA motifs. This potential has been highlighted by targeting of the triple helix present at the 3'-end of the noncoding RNA MALAT1, a transcript implicated in several human diseases. This triplex has been reported to decrease the susceptibility of the transcript to degradation and promote its cellular accumulation. While small molecules have been shown to bind to and impact the stability of the MALAT1 triple helix, the small molecule properties that lead to these structural modulations are not well understood. We designed a library utilizing the diminazene scaffold, which is underexplored but precedented for nucleic acid binding, to target the MALAT1 triple helix. We employed multiple assays to holistically assess what parameters, if any, could predict the small molecule affinity and effect on triplex stability. We designed and/or optimized competition, calorimetry, and thermal shift assays as well as an enzymatic degradation assay, the latter of which led to the discovery of bidirectional modulators of triple helix stability within the scaffold-centric library. Determination of quantitative structure-activity relationships afforded predictive models for both affinity- and stability-based assays. This work establishes a suite of powerful orthogonal biophysical tools for the evaluation of small molecule:RNA triplex interactions that generate predictive models and will allow small molecule interrogation of the growing body of disease-associated RNA triple helices.

Discoveries of RNA roles in cellular physiology and pathology are increasing the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the R NA-targeted BI oactive liga N d D atabase (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an "RNA-privileged" chemical space. Biennial updates of the database and the establishment of a website platform (rbind.chem.duke.edu) have provided new insights and tools to design small molecules based on the analyzed physicochemical and spatial properties. In this report and R-BIND 2.0 update, we refined the curation approach and ligand classification system as well as conducted analyses of RNA structure elements for the first time to identify new targeting strategies. Specifically, we curated and analyzed RNA target structural motifs to determine the properties of small molecules that may confer selectivity for distinct RNA secondary and tertiary structures. Additionally, we collected sequences of target structures and incorporated an RNA structure search algorithm into the website that outputs small molecules targeting similar motifs without a priori secondary structure knowledge. Cheminformatic analyses revealed that, despite the 50% increase in small molecule library size, the distinguishing properties of R-BIND ligands remained significantly different from that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable the rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSARs). Herein, we develop QSAR models that quantitatively predict both thermodynamic- and kinetic-based binding parameters of small molecules and the HIV-1 transactivation response (TAR) RNA model system. Small molecules bearing diverse scaffolds were screened against TAR using surface plasmon resonance. Multiple linear regression (MLR) combined with feature selection afforded robust models that allowed direct interpretation of the properties critical for both binding strength and kinetic rate constants. These models were validated with new molecules, and their accurate performance was confirmed via comparison to ensemble tree methods, supporting the general applicability of this platform.