Steric Features Research Articles

Flexi-pharma: a molecule-ranking strategy for virtual screening using pharmacophores from ligand-free conformational ensembles

Computer-aided strategies are useful for reducing the costs and increasing the success-rate in drug discovery. Among these strategies, methods based on pharmacophores (an ensemble of electronic and steric features representing the target active site) are efficient to implement over large compound libraries. However, traditional pharmacophore-based methods require knowledge of active compounds or ligand–receptor structures, and only few ones account for target flexibility. Here, we developed a pharmacophore-based virtual screening protocol, Flexi-pharma, that overcomes these limitations. The protocol uses molecular dynamics (MD) simulations to explore receptor flexibility, and performs a pharmacophore-based virtual screening over a set of MD conformations without requiring prior knowledge about known ligands or ligand–receptor structures for building the pharmacophores. The results from the different receptor conformations are combined using a “voting” approach, where a vote is given to each molecule that matches at least one pharmacophore from each MD conformation. Contrarily to other approaches that reduce the pharmacophore ensemble to some representative models and score according to the matching models or molecule conformers, the Flexi-pharma approach takes directly into account the receptor flexibility by scoring in regards to the receptor conformations. We tested the method over twenty systems, finding an enrichment of the dataset for 19 of them. Flexi-pharma is computationally efficient allowing for the screening of thousands of compounds in minutes on a single CPU core. Moreover, the ranking of molecules by vote is a general strategy that can be applied with any pharmacophore-filtering program.

Impact of Electronic and Steric Changes of Ligands on the Assembly, Stability, and Redox Activity of Cu4(μ4-S) Model Compounds of the CuZ Active Site of Nitrous Oxide Reductase (N2OR).

Model compounds have been widely utilized in understanding the structure and function of the unusual Cu4(μ4-S) active site (CuZ) of nitrous oxide reductase (N2OR). However, only a limited number of model compounds that mimic both structural and functional features of CuZ are available, limiting insights about CuZ that can be gained from model studies. Our aim has been to construct Cu4(μ4-S) clusters with tailored redox activity and chemical reactivity via modulating the ligand environment. Our synthetic approach uses dicopper(I) precursor complexes (Cu2L2) that assemble into a Cu4(μ4-S)L4 cluster with the addition of an appropriate sulfur source. Here, we summarize the features of the ligands L that stabilize precursor and Cu4(μ4-S) clusters, along with the alternative products that form with inappropriate ligands. The precursors are more likely to rearrange to Cu4(μ4-S) clusters when the Cu(I) ions are supported by bidentate ligands with 3-atom bridges, but steric and electronic features of the ligand also play crucial roles. Neutral phosphine donors have been found to stabilize Cu4(μ4-S) clusters in the 4Cu(I) oxidation state, while neutral nitrogen donors could not stabilize Cu4(μ4-S) clusters. Anionic formamidinate ligands have been found to stabilize Cu4(μ4-S) clusters in the 2Cu(I):2Cu(II) and 3Cu(I):1Cu(II) states, with both the formation of the dicopper(I) precursors and subsequent assembly of clusters being governed by the steric factor at the ortho positions of the N-aryl substituents. Phosphaamidinates, which combine a neutral phosphine donor and an anionic nitrogen donor in the same ligand, form multinuclear Cu(I) clusters unless the negative charge is valence-trapped on nitrogen, in which case the resulting dicopper precursor is unable to rearrange to a multinuclear cluster. Taken together, the results presented in this study provide design criteria for successful assembly of synthetic model clusters for the CuZ active site of N2OR, which should enable future insights into the chemical behavior of CuZ.

Medicinal Chemical Studies Based on the Theoretical Design of Bioactive Compounds

I have engaged in medicinal chemical studies based on the theoretical design of bioactive compounds. First, I present a three-dimensional structural diversity-oriented conformational restriction strategy for developing bioactive compounds based on the characteristic steric and stereoelectronic features of cyclopropane. Using this strategy, various biologically active small molecule compounds, such as receptor agonists/antagonists and enzyme inhibitors, were effectively developed. The strategy was also applied to develop versatile peptidomimetics and membrane-permeable cyclic peptides. Next, studies on Ca2+-mobilizing second messengers, cyclic ADP-ribose (cADPR) and myo-inositol trisphosphates (IP3), are described. In these studies, stable equivalents of cADPR were developed, since biological studies of cADPR have been limited due to its instability. Various potent IP3 receptor ligands, which were designed using the d-glucose structure as a bioisostere of the myo-inositol moiety of IP3, have been identified. Organic chemistry studies have also been extensively performed, because excellent organic chemistry is essential for promoting high-level medicinal chemical studies. For examples, new methods for the synthesis of chiral cyclopropanes, new radical reactions with silicon tethers, and kinetic anomeric effect-dependent stereoselective glycosidations have been developed.

Spectroscopic and Electrochemical Trends in Divalent Lanthanides through Modulation of Coordination Environment.

Due to the importance of both visible-light luminescence and lanthanides in modern society, the influence of the ligand environment on complexes of YbII were studied and compared with analogous complexes of EuII. Four ligands with systematically varied electronic and steric characteristics were used to probe the coordination environment and electronic and redox properties of the corresponding YbII-containing complexes. Strong-field nitrogenous donors gave rise to bathochromic shifts, leading to visible-light absorption by YbII. Trends in properties across the series of YbII-containing complexes were compared to trends reported for the analogous EuII-containing complexes, revealing the translatability of coordination environment effects across the divalent lanthanide series. These studies provide valuable information regarding the behavior of small and medium-sized divalent lanthanides outside of the solid state.

Toward Optimal Ru(II) Photocages: Balancing Photochemistry, Stability, and Biocompatibility Through Fine Tuning of Steric, Electronic, and Physiochemical Features.

Ru(II) complex photocages are used in a variety of biological applications, but the thermal stability, photosubstitution quantum yield, and biological compatibility of the most commonly used Ru(II) systems remain unoptimized. Here, multiple compounds used in photocaging applications were analyzed and found to have several unsatisfactory characteristics. To address these deficiencies, three new scaffolds were designed to improve key properties through modulation of a combination of electronic, steric, and physiochemical features. One of these new systems, containing the 2,2'-biquinoline-4,4'-dicarboxylic acid (2,2'-bicinchoninic acid) ligand, fulfills several of the requirements for an optimal photocage. Another complex, containing the 2-benzothiazol-2-yl-quinoline ligand, provides a scaffold for the creation of "dual action" agents.

Transfer Semihydrogenation of Alkynes Catalyzed by Imidazo[1,5-a]pyrid-3-ylidene–Pd Complexes: Positive Effects of Electronic and Steric Features on N-Heterocyclic Carbene Ligands

Abstract To investigate the catalytic utility of the imidazo[1,5-a]pyrid-3-ylidene (IPC) ligand, Pd-catalyzed transfer semihydrogenation of alkynes with formic acid as a hydrogen source was conducted. The steric bulkiness of the substituent on N2 affected the configuration of the π-allyl moiety of the precatalyst of IPC-Pd-π-allyl complexes and the robustness of the catalytic process. The catalytic activities of IPC-Pd complexes were clearly higher than those of conventional NHC-Pd complexes.

Inner- and Outer-Sphere Coordination of Acido and Neutral N,O-Donor Ligands in the Rare-Earth Metal Complexes

The data on the rare-earth metal complexes with the anionic (halides, NCS) and neutral N,O-donor ligands are systematized and generalized. The influence of the ionic radius of the complexing agent and the ligand nature (donor characteristics, steric features, nonvalent interactions) on the formation of the coordination sphere with the inner- or outer-sphere position of the ligands is monitored. The transitions of the ligands from the outer-sphere position to the first coordination sphere are considered.

Has Drug Design Augmented by Artificial Intelligence Become a Reality?

The application of artificial intelligence (AI) to drug discovery has become a hot topic in recent years. Generative molecular design based on deep learning is a particular an area of attention. Zhavoronkov etal. recently published a novel approach in which de novo molecular design based on deep learning was used to discover novel potent DDR1 kinase inhibitors. It took 21days from model building to compound design, and a total of six AI-designed compounds were synthesized and tested. The study highlights how quickly the field of AI-designed compounds is developing, and we can expect further developments in the coming years.

Crystal structures of three hexakis-(fluoroar-yloxy)cyclo-triphosphazenes.

The syntheses and crystal structures of three cyclo-triphosphazenes, all with fluorinated ar-yloxy side groups that generate different steric characteristics, viz. hexa-kis-(penta-fluoro-phen-oxy)cyclo-triphosphazene, N3P3(OC6F5)6, 1, hexa-kis-[4-(tri-fluoro-methyl)-phen-oxy]cyclo-triphosphazene, N3P3[OC6H4(CF3)]6, 2 and hexa-kis-[3,5-bis(-tri-fluoro-methyl)-phen-oxy]cyclo-triphosphazene, N3P3[OC6H3(CF3)2]6 3, are reported. Specifically, each phospho-rus atom bears either two penta-fluoro-phen-oxy, 4-tri-fluoro-methyl-phen-oxy, or 3,5-tri-fluoro-methyl-phen-oxy groups. The central six-membered phosphazene rings display envelope pucker conformations in each case, albeit to varying degrees. The maximum displacement of the 'flap atom' from the plane through the other ring atoms [0.308 (5) Å] is seen in 1, in a mol-ecule that is devoid of hydrogen atoms and which exhibits a 'wind-swept' look with all the aromatic rings displaced in the same direction. In 3 an intra-molecular C-H(aromatic)⋯F inter-action is observed. All the -CF3 groups in 2 and 3 exhibit positional disorder over two rotated orientations in close to statistical ratios. The extended structures of 2 and 3 are consolidated by C-H⋯F inter-actions of two kinds: (a) linear chains, and (b) cyclic between mol-ecules related by inversion centers. In both 1 and 3, one of the six substituted phenyl rings has a parallel-displaced aromatic π-π stacking inter-action with its respective symmetry mate with slippage values of 2.2 Å in 1 and 1.0 Å in 3. None of the structures reported here have solvent voids that could lead to clathrate formation.

The importance of the electronic and steric features of the ancillary ligands on the rate of cis–trans isomerization of olefins coordinated to palladium(0) centre. A study involving (Z)-1,2-ditosylethene as olefin model

With the aim of better understanding the mechanisms governing the spontaneous cis–trans isomerization of the olefins promoted by palladium(0) centers, we have synthesized several novel complexes bearing (Z)- or (E)-1,2-ditosylethene and a combination of other two spectator ligands including phosphines (PPh3 and 1,3,5-triaza-7-phosphaadamantane), isocyanides (i.e. 2,6-dimethylphenylisocyanide) and N-heterocyclic carbenes (NHCs). The nature of ancillary ligands heavily influences the steric and electronic features of the metal centre and consequently its interaction with olefin determines a different capability of supporting the isomerization process. The kinetic analysis and the determination of the rate constants of the isomerization suggested that both the steric and electronic factors play an important role and only an unpredictable combination can guarantee the success of the reaction.The work is completed by the structural characterization of three different Pd(0) complexes.

Synthesis, characterization, and crystal structures of organonickel(II) complexes coordinated to novel 1-bromo-2,6-bis{[(λ5-phosphanylidene)imino]methyl}benzene NCN-pincer ligands.

A novel family of four 1-bromo-2,6-bis{[(λ5-phosphanylidene)imino]methyl}benzene ligands has been synthesized and characterized. The phosphiniminomethyl substituents are decorated with either three phenyl groups, two phenyl and one cyclohexyl group, one phenyl and two cyclohexyl groups, or three cyclohexyl groups. Each ligand was metallated using zero-valent nickel through an oxidative addition to form a family of organonickel(II) complexes, namely (2,6-bis{[(triphenyl-λ5-phosphanylidene)imino]methyl}phenyl-κ3N,C1,N')bromidonickel(II) dichloromethane hemisolvate, [NiBr(C44H37N2P2)]·0.5CH2Cl2, (2,6-bis{[(cyclohexyldiphenyl-λ5-phosphanylidene)imino]methyl}phenyl-κ3N,C1,N')bromidonickel(II) diethyl ether hemisolvate, [NiBr(C44H49N2P2)]·0.5C4H10O, (2,6-bis{[(dicyclohexylphenyl-λ5-phosphanylidene)imino]methyl}phenyl-κ3N,C1,N')bromidonickel(II), [NiBr(C44H61N2P2)], and (2,6-bis{[(tricyclohexyl-λ5-phosphanylidene)imino]methyl}phenyl-κ3N,C1,N')bromidonickel(II), [NiBr(C44H73N2P2)]. This family of complexes represents a useful opportunity to investigate the impact of incrementally changing the steric characteristics of a complex on its structure and reactivity.

In vitro antitumor activity, ADME-Tox and 3D-QSAR of synthesized and selected natural styryl lactones

Prostate cancer is a common cause of death in men and a novel treating methods should be developed. In order to find a new drug for prostate cancer, a series of novel conformationally constrained analogues of (+)-goniofufurone and 7-epi-(+)-goniofufurone, as well as the newly synthesized styryl lactones containing the cinnamic acid ester groups were evaluated for in vitro cytotoxicity against prostate cancer cell (PC-3). Furthermore, prediction of physicochemical characteristics and drugability as well as in silico ADME-Tox tests of investigated compounds were performed. The 3D-QSAR model was established using the comparative molecular field analysis method. According to obtained results, the tricyclic compounds 9 and 10 had the highest potency with IC50 < 20 μM. Evaluation of structural features through 3D-QSAR model identified steric field feature on the cinnamic acid ester groups at C-7 as a crucial for the cytotoxic activity. This research suggests that most of the analysed compounds have desirable properties for drug candidates and high potential in drug development, which recommend them for further research in treatment of prostate cancer. Furthermore, obtained 3D-QSAR model is able to successfully identify styryl lactones that have significant cytotoxic activity and provide information for screening and design of novel inhibitors against PC-3 cell line that could be used as drugs in treatment of the prostate cancer.

Amorphous to high crystalline PE made by mono and dinuclear Fe-based catalysts

We designed a series of dinuclear structures (F1–F5) bearing different linkers (rigid to flexible) between the Fe centers to investigate that how they could control the catalyst behaviour and polymer properties. The dinculear structures were used for polymerization of ethylene in presence of MMAO and TiBA. Based on initial results, catalyst F2 containing methyl-substituted phenyl bridge owned the highest activity (4.9 × 106 g PE/mol Fe.h) through dinuclearity and optimum bulkiness among the structures studied. This performance was along with the greatest crystallinity (χc) of PE made by the catalyst. Polymerization at higher temperature and monomer pressure exhibited high thermal stability and performance of catalyst F2, respectively. For further structures, decreasing of effective electronic and steric features led to lower activity. In addition, not only catalyst F4 bearing the short ethylene bridge exhibited the lowest productivity, but also produced the PE containing high level of short chain branches (37.2 SCB/1000C) affording a branched microstructure of polyethylene in presence of TiBA. It could attribute to low steric and electronic effects and short distance between the centers (ethylene linker) that made it suitable and active for SCB formation. Regarding to it, the electrophilicity index (ω) of F4 also was greater that led to high capacity or propensity of the specie to accept the (macro) monomer. For this sample, virtually no χc observed in DSC and SSA thermograms. Moreover, MMAO acted as an effective cocatalyst in comparison to TiBA, according to the kinetic profiles of ethylene polymerization. The observations were in respect of strength and affinity of the cocatalysts in deactivation and reactivation of the centers at prolonged time.

The Boron‐Wittig Olefination of Aldehydes and Ketones with Bis[(pinacolato)boryl]methane: an Extended Reaction Scope

Preparation of 2,2‐disubstituted and 2‐monosubstituted alkenylboronic acid esters from aliphatic and aromatic ketones and aldehydes by the boron‐Wittig olefination with bis[(pinacolato)boryl]methane was examined and applied on the multigram scale. The influence of the substrate steric and electronic features on the overall efficiency and stereochemical outcome of the reaction was studied. Additionally, a series of diversely functionalized (hetera)cycloalkylidenemethyl and (hetera)cycloalkyl boronic acid‐derived building blocks was synthesized.

Comprehensive QSAR studies reveal structural insights into the NR2B subtype selective benzazepine derivatives as N-Methyl-d-Aspartate receptor antagonists

NMDA receptors are considered as high profile therapeutic target in the treatment of pain and neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's disease. NR2 subunit of NMDA receptor divided into four subunits i.e. NR2A, NR2B, NR2C and NR2D. Restricted distribution of NR2B subunit in the brain makes it potential target. In the present study, new structural insights into benzazepine derivatives as NR2B selective NMDA receptor antagonists have been reported using QSAR modelling. Total five QSAR models were developed using various statistical methods. 2D-QSAR models showed that chi3 and SsssNE-index descriptors are crucial for NMDA receptor antagonistic activity. Chi3 descriptor relates with non-hydrogen heteroatom connected with two or three bonds and SsssNE-index descriptor deals with Electrotopological state indices for number of nitrogen atom connected with three single bonds. Both the descriptors were negatively correlated with all the developed 2D-QSAR models. Significance of these descriptors is extensively studied in present work. In 3D-QSAR studies, steric and electrostatic fields were found to be important for antagonistic effect on NMDA receptors. 3D-QSAR studies clarify the substitution pattern of R group on nitrogen atom of benzazepine core. The substitutions with high electropositive with less or medium steric character are favourable for the activity. All developed models were critically validated to establish their reliability and accuracy for prediction of binding affinity of benzazepine derivatives towards NR2B subunit of NMDA receptor. The present study offered not only highly predictive and reliable QSAR models for benzazepine derivatives but also revealed some of the vital structural observations required for their higher binding affinity towards NR2B subunit of NMDA receptors.

Accumulative Charging of Redox-Active Side-Chain-Modified Polymers: Experimental and Computational Insights from Oligo- to Polymeric Triarylamines

The anionic polymerization of three functionalized styrenic triarylamines is presented, including a series of oligomers to analyze the configurational and conformational details. Advanced NMR techniques were utilized for end group analysis to enable definite peak assignments. An inferior preference for stereoregularity was found, i.e., the formation of diastereomers for each new chiral center (ca. 60/40 ratio). Chemical shift analysis revealed the degree of conformational flexibility, which is governed by the three nearest repeating units. The electrochemical properties were detailed by semidifferential analysis of conventional cyclovoltammetric data, showing fully reversible oxidation in all cases. The data deconvolution resolved the individual formal oxidation steps, which revealed the expected entropic peak broadening and additional contributions in a consistent manner. The effect was particularly pronounced for the densely decorated polymer, which displayed an anodic shift (+0.1) V for ca. 30% of all redox-active units. The origin was assigned to an electrostatic penalty due to the diminished charge compensation by the electrolyte-excluded volume. For example, microelectrode measurements of the trimer also revealed a slower transfer rate of the third oxidation step. A series of density functional theory calculations corroborated the assignments of accumulative charging, i.e., reproduced the steric and electrochemical features in good agreement. Spectroelectrochemical measurements revealed the occurrence of side reactions at higher applied potentials for the polymers, but not in the case of the oligomers. The presented analysis is expected to complement the general electrochemical characterization of redox-active polymers, e.g., to elucidate the precise role of solubilizing substituents or the architecture dictated by spacing units or upon copolymerization with various monomers.

Synthesis of 1,1,2-trisubstituted cyclopropane nucleosides in enantiomerically pure forms

Due to the unique rigid and small steric feature of cyclopropane, cyclopropane nucleosides (CPNs) in which the ribose (deoxyribose) of nucleosides are replaced by a hydroxy-substituted cyclopropane, are of great biological interest. Novel 1,1,2-trisubstituted cyclopropane nucleosides were synthesized in enantiomerically pure forms as potential antiviral agents. In the synthesis, two cyclopropane tosylates, which were prepared from chiral cyclopropane lactones previously reported by us, were used effectively as common intermediates for the CPNs. These CPNs are also potentially useful as nucleoside units to incorporate into oligonucleotides in nucleic acids chemotherapy studies.

Importance of monodentate mono-ligand designs in developing N-stabilized Pd catalysts for efficient ambient temperature C[sbnd]C coupling: Donor strengths and steric features

Unfriendly temperature profiles and costs of carbon coupling catalysis, which pose challenge to both synthetic organic chemists as well as industrial applicability, motivated our design of new monodentate N-donors as support ligands for the purpose of constructing ambient temperature precatalysts that are molecularly close to the hypothetical active forms. Therefore, a series of sterically varied monodentate N-donor imidazoles (1–7) and oxazoles (8–9) have been synthesized and their N-donor strengths, which were estimated as pKas, are systematically varied from 0.9 to 8.5 by substituent variations. Eleven target mono-ligand complexes (1-PdCl2MeCN – 9-PdCl2MeCN, 6-PdCl2PhCN and 7-PdCl2PhCN) and six trans-bis-ligand complexes (12-PdCl2, 22-PdCl2, 32-PdCl2, 62-PdCl2, 12-Pd(OAc)2 and 22-Pd(OAc)2) were isolated and catalytically studied along with PdI2(PPh3)2. Results of coupling reactions, which were conducted both via in situ ‘Pd(II) salt + ligand’ approach and by use of the precatalysts, show that the mono-ligand precatalyst designs (1-PdCl2MeCN – 9-PdCl2MeCN, 6-PdCl2PhCN and 7-PdCl2PhCN) represent a true catalyst improvement initiative among the phosphine-free catalyst community; i.e. yields approaching 100% (TOF ≈ 2000) at 0.2 mol % catalyst loading, 45 °C and within 15 min. On the other hand, the complexes with trans-bis-ligand coordination were inactive at ambient temperatures. Therefore, it was concluded that coordinative saturation, which results from implementing two or more ligand equivalents or use of polydentate ligands on palladium, should be strongly discouraged. Such saturation necessitates the undesirable and avoidable high temperature necessities, long reflux durations and needlessly high catalyst loadings. Correlation between catalyst activity and donor strengths or steric properties were analysed leading to important conclusions. The catalyst design also supported coupling of activated aryl chlorides from 60 °C while Heck coupling activities were observed only at the early minutes of reactions.

Porosity Switching in Polymorphic Porous Organic Cages with Exceptional Chemical Stability

AbstractPorous solids that can be switched between different forms with distinct physical properties are appealing candidates for separation, catalysis, and host–guest chemistry. In this regard, porous organic cages (POCs) are of profound interest because of their solution‐state accessibility. However, the application of POCs is limited by poor chemical stability. Synthesis of an exceptionally stable imine‐linked (4+6) porous organic cage (TpOMe‐CDA) is reported using 2,4,6‐trimethoxy‐1,3,5‐triformyl benzene (TpOMe) as a precursor aldehyde. Introduction of the ‐OMe functional group to the aldehyde creates significant steric and hydrophobic characteristics in the environment around the imine bonds that protects the cage molecules from hydrolysis in the presence of acids or bases. The electronic effect of the ‐OMe group also plays an important role in enhancing the stability of the reported POCs. As a consequence, TpOMe‐CDA reveals exceptional chemical stability in neutral, acidic and basic conditions, even in 12 m NaOH. Interestingly, TpOMe‐CDA exists in three different porous and non‐porous polymorphic forms (α, β, and γ) with respect to differences in crystallographic packing and the orientation of the flexible methoxy groups. All of the polymorphs retain their crystallinity even after treatment with acids and bases. All the polymorphs of TpOMe‐CDA differ significantly in their properties as well as morphology and could be reversibly switched in the presence of an external stimulus.

Porosity Switching in Polymorphic Porous Organic Cages with Exceptional Chemical Stability.

Porous solids that can be switched between different forms with distinct physical properties are appealing candidates for separation, catalysis, and host-guest chemistry. In this regard, porous organic cages (POCs) are of profound interest because of their solution-state accessibility. However, the application of POCs is limited by poor chemical stability. Synthesis of an exceptionally stable imine-linked (4+6) porous organic cage (TpOMe-CDA) is reported using 2,4,6-trimethoxy-1,3,5-triformyl benzene (TpOMe) as a precursor aldehyde. Introduction of the -OMe functional group to the aldehyde creates significant steric and hydrophobic characteristics in the environment around the imine bonds that protects the cage molecules from hydrolysis in the presence of acids or bases. The electronic effect of the -OMe group also plays an important role in enhancing the stability of the reported POCs. As a consequence, TpOMe-CDA reveals exceptional chemical stability in neutral, acidic and basic conditions, even in 12 m NaOH. Interestingly, TpOMe-CDA exists in three different porous and non-porous polymorphic forms (α, β, and γ) with respect to differences in crystallographic packing and the orientation of the flexible methoxy groups. All of the polymorphs retain their crystallinity even after treatment with acids and bases. All the polymorphs of TpOMe-CDA differ significantly in their properties as well as morphology and could be reversibly switched in the presence of an external stimulus.