Discovery of new small-molecule cyclin-dependent kinase 6 inhibitors through computational approaches

Molecular Diversity - Excessive cell proliferation due to cell cycle disorders is one of the hallmarks of breast cancer. Cyclin-dependent kinases (CDKs), which are involved in the transition of the...     

Identification of novel potential HIF-prolyl hydroxylase inhibitors by in silico screening

Suppression of HIF-prolyl hydroxylase (PHD) activity by small-molecule inhibitors leads to the stabilization of hypoxia inducible factor and has been recognized as promising drug target for the treatment of ischemic diseases. In this study, pharmacophore-based virtual screening and molecular docking approaches were concurrently used with suitable modifications to identify target-specific PHD inhibitors with better absorption, distribution, metabolism, and excretion properties and to readily minimize false positives and false negatives. A customized method based on the active site information of the enzyme was used to generate a pharmacophore hypothesis (AAANR). The hypothesis was validated and utilized for chemical database screening and the retrieved hit compounds were subjected to molecular docking for further refinement. AAANR hypothesis comprised three H-bond acceptor, one negative ionizable group and one aromatic ring feature. The hypothesis was validated using decoy set with a goodness of fit score of 2 and was used as a 3D query for database screening. After manual selection, molecular docking and further refinement based on the molecular interactions of inhibitors with the essential amino acid residues, 18 hits with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as excellent PHD inhibitors. The best pharmacophore hypothesis, AAANR, contains chemical features required for the effective inhibition of PHD. Using AAANR, we have identified 18 potential and diverse virtual leads, which can be readily evaluated for their potency as novel inhibitors of PHD. It can be concluded that the combination of pharmacophore, molecular docking, and manual interpretation approaches can be more successful than the traditional approach alone for discovering more effective inhibitors.     

Synthesis and biological evaluation of 1,2,4-triazolidine-3-thiones as potent acetylcholinesterase inhibitors: in vitro and in silico analysis through kinetics,chemoinformatics and computational approaches

Molecular Diversity - We have designed and synthesized a novel acidic ionic liquid and explored its catalytic efficiency for the synthesis of 1,2,4-triazolidine-3-thione derivatives. A simple...     

Combinatorial approaches to inhibitors of VLA-4: Piperazine-peptoid-bisarylureas

A combinatorial approach towards identifying inhibitors of VALA-4 was investigated. A library of piperazine-peptoid-bisarylureas was assembled in solid phase and screening in the novel v-well assay enabled the identificationof active compounds     

On the mechanism of xylan pyrolysis by combined experimental and computational approaches

Pyrolysis is the initial stage of biomass combustion, whereas, the pyrolysis mechanism of biomass, especially the hemicellulose component, is still not well elucidated. Herein, a common hemicellulose polysaccharide, xylan, was investigated to reveal the evolution of volatiles and solid residue through combined thermogravimetry-Fourier transform infrared spectroscopy (TG-FTIR) and in-situ diffuse reflectance infrared Fourier transform spectroscopy (in-situ DRIFT) techniques. Quantum chemistry calculation was also conducted to analyze the primary xylan pyrolysis mechanism by using a long-chain xylan model which was built based on the structural characterization of xylan. The experimental results indicated that the functional groups in solid-phase evolved intensively during the main weight loss zone (200–350 °C), leading to the violent release of volatiles. The decomposition of branches, especially the arabinose unit, was prior to that of the backbone, with relatively low energy barriers and high rate constants. The initial enhancement of CO vibration in solid-phase above 200 °C derived from the formation of the furanose unit. Both dehydration and breakage of glycosidic bonds were responsible for the formation of CC bond in solid-phase from 300 °C. The cracking of the 4-O-Me group resulted in the release of aldehydes to gas-phase in the main weight loss zone (200–350 °C). The scission of the whole 4-O-MeGlc unit and/or the rupture of the uronic acid group led to the gas-phase CO bond formation.     

Designing solar-cell absorber materials through computational high-throughput screening

Although the efficiency of CH_3 NH_3 PI_3 has been refreshed to 25.2%,stability and toxicity remain the main challenges for its applications.The search for novel solar-cell absorbers that are highly stable,non-toxic,inexpensive,and highly efficient is now a viable research focus.In this review,we summarize our recent research into the high-throughput screening and materials design of solar-cell absorbers,including single perovskites,double perovskites,and materials beyond Perovskites.BazrS_3(single perovskite),Ba_2 BiNbS_6(double perovskite),HgAl_2 Se_4(spinel),and IrSb_3(skutterudite)were discovered to be potential candidates in terms of their high stabilities,appropriate bandgaps,small carrier effective masses,and strong optical absorption.     

Discovery of enzyme inhibitors through combinatorial chemistry

Summary This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.     

Benzisoxazole 2‐oxides as novel UV absorbers and photooxidation inhibitors

Compounds with strong absorptions in the ultraviolet (UV) region of the spectrum, particularly the UVA and UVB, have seen much interest as UV screeners or absorbers in a wide variety of commercial products. A series of benzisoxazole 2‐oxides have been synthesized and characterized by UV–vis spectroscopy. A number of derivatives have been shown to posses moderate to strong molar absorption coefficients in the UVB range (ca. 300 nm), the strongest being those derived from benzophenones. Three other derivatives containing additional electron withdrawing groups showed strong molar absorption coefficients in the UVA (ca. 340 nm). Solvent effects on the parent derivatives show changes in the molar absorption coefficients with little changes in the λ_max values. Preliminary studies of these compounds as potential additives to prevent photooxidation of polystyrene showed considerable inhibition of polymer degradation with the parent unsubstituted benzisoxazole 2‐oxide compounds being the most effective. Copyright © 2013 John Wiley & Sons, Ltd.     

Influence of the source's energy fluctuation on computational ghost imaging and effective correction approaches

We investigate the influence of the source's energy fluctuation on both computational ghost imaging and computational ghost imaging via sparsity constraint,and if the reconstruction quality will decrease with the increase of the source's energy fluctuation.In order to overcome the problem of image degradation,a correction approach against the source's energy fluctuation is proposed by recording the source's fluctuation with a monitor before modulation and correcting the echo signal or the intensity of computed reference light field with the data recorded by the monitor.Both the numerical simulation and experimental results demonstrate that computational ghost imaging via sparsity constraint can be enhanced by correcting the echo signal or the intensity of computed reference light field,while only correcting the echo signal is valid for computational ghost imaging.     

Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors

Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r ² = 0.642, SD = 0.65, F = 82.7, P = 7.617 e − 12). The test set correlation is characterized by PLS factors (Q ² _ext = 0.841, RMSE = 0.24,Pearson−R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.     

Dehydroabietylamine-based thiazolidin-4-ones and 2-thioxoimidazolidin-4-ones as novel tyrosyl-DNA phosphodiesterase 1 inhibitors

Molecular Diversity - Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in...     

Imaging through aberrating imaging with media by computational ghost incoherent light

we demonstrate a series of experiments on imaging through both stationary aberrating media and moving aberrating media by computational ghost imaging （CGI）. An incoherent LED light source is used instead of the common pseudothermal light source （laser light passing through a rotating ground glass）. A digital micromirror device is used as a simple spatial light modulator to perform CGI. Moreover. a digital filtering method is introduced to improve imaging quality through moving aberrating media. This imaging modality may have potential applications in medicine and astronomy.     

Imaging through aberrating media by computational ghost imaging with incoherent light

We demonstrate a series of experiments on imaging through both stationary aberrating media and moving aberrating media by computational ghost imaging(CGI).An incoherent LED light source is used instead of the common pseudothermal light source(laser light passing through a rotating ground glass).A digital micromirror device is used as a simple spatial light modulator to perform CGI.Moreover,a digital filtering method is introduced to improve imaging quality through moving aberrating media.This imaging modality may have potential applications in medicine and astronomy.     

A computational characterization of N2@C60

Recent observations of N₂@C₆₀ are supported computationally. The geometry is optimized at the B3LYP/3-21G and PW91/3-21G levels. The lowest-energy structure has the N₂ unit oriented towards a pair of parallel pentagons so that the complex exhibits D_5d symmetry. Single-point energy calculations are further carried out at the B3LYP/6-31G*, PW91/6-31G* and MP2?=?FC/6-31G* levels and corrected for the basis set superposition error (BSSE). The MP2?=?FC/6-31G* treatment with the BSSE correction gives a stabilization energy of -9.3?kcal?mol^?1, whereas DFT approaches mostly fail to produce a stabilization. The entropy term for the encapsulation is also evaluated and leads to a standard Gibbs energy change upon encapsulation at room temperature of -3.3?kcal?mol^?1. The computed structural and vibrational characteristics are also reported.     

Development of novel materials through interface engineering

The impact of interfaces in the processing and properties of polycrystalline material is briefly discussed. The local properties of the interfacial layer are considered in terms of composition, structure and related properties that differ substantially from those of the bulk phase. It has been postulated that novel materials with desired properties for specific industrial applications may be processed through interface engineering rather than through bulk chemistry. This paper considers the impact of interfaces on the properties of materials for technological applications, such as electrochemical devices for reduction of greenhouse gases, through energy conversion and environmental monitoring. The procedures that may be applied for the modification of interfacial chemistry are considered.     

Psoriatic arthritis: Pathogenesis and novel immunomodulatory approaches to treatment

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis and psoriasis. PsA runs a variable course, from mild synovitis to severe, progressive, erosive arthropathy. The pathogenesis of PsA involves alteration in the components of the immune response, although the exact cause of PsA is unknown. A number of patients with severe peripheral arthritis fail to respond to standard conventional therapy. Advances in biotechnology and in our understanding of the immunopathogenesis of PsA have led to great interest and progress in regards to biologic treatments for PsA. Notable success achieved with recently introduced biologic therapies has paved the way for further research and develpoment of additional therapies that should improve outcomes for affected patients.     

Toward a computational framework for cognitive biology: Unifying approaches from cognitive neuroscience and comparative cognition

Progress in understanding cognition requires a quantitative, theoretical framework, grounded in the other natural sciences and able to bridge between implementational, algorithmic and computational levels of explanation. I review recent results in neuroscience and cognitive biology that, when combined, provide key components of such an improved conceptual framework for contemporary cognitive science. Starting at the neuronal level, I first discuss the contemporary realization that single neurons are powerful tree-shaped computers, which implies a reorientation of computational models of learning and plasticity to a lower, cellular, level. I then turn to predictive systems theory (predictive coding and prediction-based learning) which provides a powerful formal framework for understanding brain function at a more global level. Although most formal models concerning predictive coding are framed in associationist terms, I argue that modern data necessitate a reinterpretation of such models in cognitive terms: as model-based predictive systems. Finally, I review the role of the theory of computation and formal language theory in the recent explosion of comparative biological research attempting to isolate and explore how different species differ in their cognitive capacities. Experiments to date strongly suggest that there is an important difference between humans and most other species, best characterized cognitively as a propensity by our species to infer tree structures from sequential data. Computationally, this capacity entails generative capacities above the regular (finite-state) level; implementationally, it requires some neural equivalent of a push-down stack. I dub this unusual human propensity “dendrophilia”, and make a number of concrete suggestions about how such a system may be implemented in the human brain, about how and why it evolved, and what this implies for models of language acquisition. I conclude that, although much remains to be done, a neurally-grounded framework for theoretical cognitive science is within reach that can move beyond polarized debates and provide a more adequate theoretical future for cognitive biology.