51 research outputs found
Domain-wall melting as a probe of many-body localization
Motivated by a recent optical-lattice experiment by Choi et al.[Science 352,
1547 (2016)], we discuss how domain-wall melting can be used to investigate
many-body localization. First, by considering noninteracting fermion models, we
demonstrate that experimentally accessible measures are sensitive to
localization and can thus be used to detect the delocalization-localization
transition, including divergences of characteristic length scales. Second,
using extensive time-dependent density matrix renormalization group
simulations, we study fermions with repulsive interactions on a chain and a
two-leg ladder. The extracted critical disorder strengths agree well with the
ones found in existing literature.Comment: 4+2 pages, 4+2 figure
Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery—Construction of a Diversity-Optimized Halogen-Enriched Fragment Library
Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by VmaxPred
Switching Between Bicyclic and Linear Peptides — The Sulfhydryl-Specific Linker TPSMB Enables Reversible Cyclization of Peptides
Phage display-selected bicyclic peptides have already shown their great potential for the development as bioactive modulators of therapeutic targets. They can provide enhanced proteolytic stability and improved membrane permeability. Molecular design of new linker molecules has led to a variety of new synthetic approaches for the generation of chemically constrained cyclic peptides. This diversity can be useful for the development of novel peptide-based therapeutic, diagnostic, and scientific tools. Herein, we introduce 1,3,5-tris((pyridin-2-yldisulfanyl)methyl)benzene (TPSMB) as a planar, trivalent, sulfhydryl-specific linker that facilitates reversible cyclization and linearization via disulfide bond formation and cleavage of bicyclic peptides of the format CXnCXnC, where X is any proteinogenic amino acid except cysteine. The rapid and highly sulfhydryl-specific reaction of TPSMB under physiological conditions is demonstrated by selecting bicyclic peptide binders against c-Jun N-terminal kinase 3 (JNK3) as a model target. While model peptides remain stably cyclized for several hours in presence of typical blood levels of glutathione in vitro, high cytosolic concentrations of glutathione linearize these peptides completely within 1 h. We propose that reversible linkers can be useful tools for several technical applications where target affinity depends on the bicyclic structure of the peptide
Types of Corruption in Small and Micro Enterprises (SMEs) in Ibadan, Nigeria
Corruption is a phenomenon that manifests in various types and forms especially among operators of Small and Micro Enterprises (SMEs). Many actions of the operators which constitute corrupt practices often tend to be overlooked in spite of their grave consequences for the success SMEs in Nigeria. The fight against corruption in Nigeria is more concentrated in the formal sector. This study was, therefore, designed to investigate various forms in which corrupt practices are carried out among Small and Micro Enterprises in Ibadan, Nigeria. Business owners, their employees, apprentices and consumers constituted the study population. Primary data were collected using questionnaire administered on 200 business owners, 150 employees and 150 apprentices randomly chosen in five business districts in Ibadan; and the conduct of 10 in-depth interviews with purposively selected participants. Quantitative data were analysed at uni-variate level using simple percentages and frequencies while qualitative data were content analysed. Findings from the study revealed that corrupt practices were rampant among actors in SMEs and the common types of corrupt practices included stealing (60%), deception of customers (78.4%), tax evasion (62%), sale of fake products (76%), sale of expired products (65.2%), tampering with measurement scales (69.6%), bribery (82.4%), and poor service delivery (73%). The study concludes that the level of corruption in SMEs calls for concern and government should extend the fight against corruption to the informal sector in Nigeria
Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery-Construction of a Diversity-Optimized Halogen-Enriched Fragment Library
Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by VmaxPred.</p
Scaffold Effects on Halogen Bonding Strength
Halogen bonds have become increasingly
popular interactions in
molecular design and drug discovery. One of the key features is the
strong dependence of the size and magnitude of the halogen’s
σ-hole on the chemical environment of the ligand. The term σ-hole
refers to a region of lower electronic density opposite to a covalent
bond, e.g., the C-X bond. It is typically (but not always) associated
with a positive electrostatic potential in close proximity to the
extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing
heterocycles, halogenated systematically by chlorine, bromine, or
iodine, yielding 468 different ligands that are used to exemplify
scaffold effects on halogen bonding strength. As a template interaction
partner, we have chosen N-methylacetamide representing
the ubiquitously present protein backbone. Adduct formation energies
were obtained at a MP2/TZVPP level of theory. We used the local maximum
of the electrostatic potential on the molecular surface in close proximity
to the σ-hole, VS,max, as a descriptor
for the magnitude of the positive electrostatic potential characterizing
the tuning of the σ-hole. Free optimization of the complexes
gave reasonable correlations with VS,max but was found to be of limited use because considerable numbers
of chlorinated and brominated ligands lost their halogen bond or showed
significant secondary interactions. Thus, starting from a close to
optimal geometry of the halogen bond, we used distance scans to obtain
the best adduct formation energy for each complex. This approach provided
superior results for all complexes exhibiting correlations with R2 > 0.96 for each individual halogen. We evaluated the dependence
of VS,max from the molecular surface onto
which the positive electrostatic potential is projected, altering
the isodensity values from 0.001 au to 0.050 au. Interestingly, the
best overall fit using a third-order polynomial function (R2 = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between
all halogens was obtained for VS,max calculated
from an isodensity surface at 0.014 au
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