The Rise and Fall of a Scaffold: A Trend Analysis of Scaffolds in the Medicinal Chemistry Literature

Scaffolds are a core concept in medicinal chemistry, and they can be the focus of multiple independent development efforts over an extended period. Thus, scaffold associated properties can vary over time, possibly showing consistently increasing or decreasing trends. We posit that such trends characterize the attention that the community pays to a scaffold. In this study, we employed data from ChEMBL20 to examine the evolution of scaffold features, such as enumerated compounds, biological activity, and liabilities, over 17 years. Our analysis highlights that certain properties such as enumerated compounds, but not liabilities, show statistically significant increasing trends for some scaffolds. We also attempt to explain why a scaffold receives more attention over time and highlight that obvious aspects such as synthetic feasibility do not explicitly drive attention. In summary, trend analyses of scaffold properties could support scaffold selection and prioritization in small molecule development projects

The Rise and Fall of a Scaffold: A Trend Analysis of Scaffolds in the Medicinal Chemistry Literature

Scaffolds are a core concept in medicinal chemistry, and they can be the focus of multiple independent development efforts over an extended period. Thus, scaffold associated properties can vary over time, possibly showing consistently increasing or decreasing trends. We posit that such trends characterize the attention that the community pays to a scaffold. In this study, we employed data from ChEMBL20 to examine the evolution of scaffold features, such as enumerated compounds, biological activity, and liabilities, over 17 years. Our analysis highlights that certain properties such as enumerated compounds, but not liabilities, show statistically significant increasing trends for some scaffolds. We also attempt to explain why a scaffold receives more attention over time and highlight that obvious aspects such as synthetic feasibility do not explicitly drive attention. In summary, trend analyses of scaffold properties could support scaffold selection and prioritization in small molecule development projects

[[alternative]]Thiourea compounds and method for inhibiting hepatitis c virus infection

[[abstract]]本發明提供一種硫尿化合物，具有下列化學式(I)：其中每一R1 、R2 與R3 獨立地包括氫、C1 －C10 烷基、C2 －C10 烯基、C2 －C10 炔基、C3 －C20 環烷基、C3 －C20 環烯基、C1 －C20 異環烷基、C1 －C20 異環烯基、芳基或異芳基或R1 與R2 與一氮原子鍵結形成C3 －C20 異環烷基或R2 與R3 與二氮原子鍵結形成C3 －C20 異環烷基；每一A1 與A2 獨立地包括芳基或異芳基；每一X、Y與Z獨立地包括O、S、S(O)、S(O)2 、N(Ra )、C(Ra Rb )、C1 －C10 烷基、C2 －C10 烯基、C2 －C10 炔基、C3 －C20 環烷基、C1 －C20 異環烷基、芳基或異芳基，每一Ra 與Rb 獨立地包括氫、C1 －C10 烷基、C3 －C20 環烷基、C1 －C20 異環烷基、芳基或異芳基；每一m與n獨立地為1、2、3、4或5；以及每一x、y與z獨立地為0或1。該硫尿化合物可用於抑制C型肝炎病毒感染。A thiourea compound of formula (I) is provided,wherein each of R1 , R2 and R3 , independently, is H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C3 -C20 cycloalkyl, C3 -C20 cycloalkenyl, C1 -C20 heterocycloalkyl, C1 -C20 heterocycloalkenyl, aryl or heteroaryl, or R1 and R2 , together with the nitrogen atom to which they are bonded, are C3 -C20 heterocycloalkyl, or R2 and R3 , together with the two nitrogen atoms to which they are bonded and the carbon atom bonded to both of the two nitrogen atoms, are C3 -C20 heterocycloalkyl, each of A1 and A2 , independently, is aryl or heteroaryl, each of X, Y, and Z, independently, is O, S, S(O), S(O)2 , N(Ra ), C(Ra Rb ), C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C3 -C20 cycloalkyl, C1 -C20 heterocycloalkyl, aryl or heteroaryl, in which each of Ra and Rb , independently, is H, C1 -C10 alkyl, C3 -C20 cycloalkyl, C1 -C20 heterocycloalkyl, aryl or heteroaryl, each of m and n, independently, is 1, 2, 3, 4 or 5, and each of x, y and z, independently, is 0 or 1. The compound can be used to inhibit hepatitis C virus infection

Particle Deposition on Microporous Membranes Can Be Enhanced or Reduced by Salt Gradients

Colloidal particle deposition on membranes is a continuing scientific and technological challenge. In this paper we examine the role of a previously unexplored phenomenondiffusiophoretic particle transport toward a membranein relation to fouling. Diffusiophoresis is an electrokinetic transport mechanism that arises in salt gradients, especially when the ions have different diffusion coefficients. Through experiments conducted with salt diffusing across microdialysis membranes, with no advection, we show experimentally that diffusiophoresis induces colloidal deposition on the surface of microporous surfaces. We used transient salt (NaCl, KCl, LiCl) gradients and fundamental electrokinetic modeling to assess the role of diffusiophoresis in colloidal fouling. Based on (i) difference in diffusion coefficients of ions, (ii) zeta potential on the particles, and (iii) ionic gradient applied across the walls of the membrane, colloidal fouling could be both quantitatively and qualitatively predicted. Our understanding enabled us to stop particle deposition by adding calcium carbonate outside the membrane, which generates a stronger electric field in a direction opposite to that created by salt diffusing from the membrane. We propose that accounting for this diffusiophoretic mode of particle deposition is important in understanding membrane fouling

Chemotaxis of Molecular Dyes in Polymer Gradients in Solution

Chemotaxis provides a mechanism for directing the transport of molecules along chemical gradients. Here, we show the chemotactic migration of dye molecules in response to the gradients of several different neutral polymers. The magnitude of chemotactic response depends on the structure of the monomer, polymer molecular weight and concentration, and the nature of the solvent. The mechanism involves cross-diffusion up the polymer gradient, driven by favorable dye–polymer interaction. Modeling allows us to quantitatively evaluate the strength of the interaction and the effect of the various parameters that govern chemotaxis

Modulation of Spatiotemporal Particle Patterning in Evaporating Droplets: Applications to Diagnostics and Materials Science

Spatiotemporal particle patterning in evaporating droplets lacks a common design framework. Here, we demonstrate autonomous control of particle distribution in evaporating droplets through the imposition of a salt-induced self-generated electric field as a generalized patterning strategy. Through modeling, a new dimensionless number, termed “capillary-phoresis” (CP) number, arises, which determines the relative contributions of electrokinetic and convective transport to pattern formation, enabling one to accurately predict the mode of particle assembly by controlling the spontaneous electric field and surface potentials. Modulation of the CP number allows the particles to be focused in a specific region in space or distributed evenly. Moreover, starting with a mixture of two different particle types, their relative placement in the ensuing pattern can be controlled, allowing coassemblies of multiple, distinct particle populations. By this approach, hypermethylated DNA, prevalent in cancerous cells, can be qualitatively distinguished from normal DNA of comparable molecular weights. In other examples, we show uniform dispersion of several particle types (polymeric colloids, multiwalled carbon nanotubes, and molecular dyes) on different substrates (metallic Cu, metal oxide, and flexible polymer), as dictated by the CP number. Depending on the particle, the highly uniform distribution leads to surfaces with a lower sheet resistance, as well as superior dye-printed displays

A temperature sensitive (ts) allele of the SV40 Large T antigen (LTag) fused to EGFP engages the PQC machinery.

<p>a) Outline of the fluorescent PQC reporter system in mammalian cells. LTR: Retroviral Long Terminal Repeat, CMV: immediate early cytomegalovirus promoter, LTag; SV40 Large T antigen, ts: temperature sensitive, IRES: internal ribosome entry site, NLS: nuclear localization signal. b) U2OS cells stably expressing either a wild-type (WT) or a temperature-sensitive (ts) allele of LTag fused to EGFP were grown at 33.5°C and then shifted to 38.5°C for the indicated amount of time. Total cell lysates were probed in Western Blotting with the indicated antibodies. c) Same as b), except that cells were either treated with DMSO or the proteasome inhibitor MG132 at a final concentration of 2 µM.</p

The PQC assay quantitatively measures the degradation of LTag(ts)-EGFP at the restrictive temperature.

<p>a) U2OS cells stably expressing LTag(ts)-EGFP and NLS-DsRedExpress2 (NLS-Red) were grown in 384 well-plates for 48 hrs at 33.5°C and then shifted at the indicated temperatures for 24 hrs. DRAQ5 stains the DNA and is used to identify the nuclei. Cells were fixed in paraformaldehyde and imaged sequentially at 488 nm, 568 nm, and 640 nm (40× magnification, 1 imaging field). Scale bar: 20 µm b) Montage of 12 40× fields representing the entire population of cells in a 384-well. Scale bar: 100 µm. c) Same as b), except that cells were treated with MG132 (250 nM). (-) indicates the untreated control. d) Same as b) except that U2OS cells stably expressing the LTag(WT)-EGFP and NLS-DsRedExpress2 were used. e) Histograms representing the quantification of nuclear fluorescence intensities and the EGFP/DsRedExpress2 ratio. Typically >300 cells were imaged per well. Values represent averages +/− S.E.M of 4 experiments.</p

Genome-wide siRNA screen for PQC factors.

<p>a) U2OS cells expressing LTag(ts)-EGFP and NLS-DsRedExpress2 were screened against a library containing ∼18, 000 siRNA pools targeting human protein-coding genes. The histogram represents the distribution of the EGFP/DsRedExpress2 ratio robust Z-score measured for each siRNA pool. The location of the EGFP/DsRedExpress2 ratio robust Z-score threshold used to select positive siRNA pools is indicated. b) Analysis of hits from the genome-wide PQC screen reveals significant enrichment for translation/translation initiation processes. Enrichment analysis was conducted using GeneGo Process Networks with a false discovery rate (FDR) of 0.05. 9 of the top 84 genes are found within this network, including EIF3A, EIF3F, NHP2-like protein 1 (NH2L1), NOP56/NOL5A, RPS13, RPS24, RPS28, RPS4X and RPS8. c) U2OS cells expressing LTag(ts)-EGFP or LTag(WT)-EGFP and NLS-DsRedExpress2 were independently transfected for validation with 4 siRNAs targeting 71 of the genes that were scored as positive in the primary PQC screen. Positive hits in this secondary screen were classified as genes whose silencing by at least two independent oligo siRNAs had a EGFP/DsRedExpress2 ratio larger than 140% of the value obtained by transfection of a non-targeting siRNA oligo. The table shows such positive genes in the LTag(ts)-EGFP or LTag(WT)-EGFP expressing cell lines, respectively.</p