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https://www.readbyqxmd.com/read/28319812/exploring-sequence-space-harnessing-chemical-and-biological-diversity-towards-new-peptide-leads
#1
REVIEW
Richard Obexer, Louise J Walport, Hiroaki Suga
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable...
March 17, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28319747/integration-of-in-silico-methods-and-computational-systems-biology-to-explore-endocrine-disrupting-chemical-binding-with-nuclear-hormone-receptors
#2
P Ruiz, A Sack, M Wampole, S Bobst, M Vracko
Thousands of potential endocrine-disrupting chemicals present difficult regulatory challenges. Endocrine-disrupting chemicals can interfere with several nuclear hormone receptors associated with a variety of adverse health effects. The U.S. Environmental Protection Agency (U.S. EPA) has released its reviews of Tier 1 screening assay results for a set of pesticides in the Endocrine Disruptor Screening Program (EDSP), and recently, the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) data...
March 9, 2017: Chemosphere
https://www.readbyqxmd.com/read/28319389/potential-antiosteoporotic-natural-product-lead-compounds-that-inhibit-17%C3%AE-hydroxysteroid-dehydrogenase-type-2
#3
Anna Vuorinen, Roger T Engeli, Susanne Leugger, Fabio Bachmann, Muhammad Akram, Atanas G Atanasov, Birgit Waltenberger, Veronika Temml, Hermann Stuppner, Liselotte Krenn, Sylvin B Ateba, Dieudonné Njamen, Rohan A Davis, Alex Odermatt, Daniela Schuster
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ(4)-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature...
March 20, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28318014/-solvent-hydrogen-bond-occlusion-a-new-model-of-polar-desolvation-for-biomolecular-energetics
#4
Andrea Bazzoli, John Karanicolas
Water engages in two important types of interactions near biomolecules: it forms ordered "cages" around exposed hydrophobic regions, and it participates in hydrogen bonds with surface polar groups. Both types of interaction are critical to biomolecular structure and function, but explicitly including an appropriate number of solvent molecules makes many applications computationally intractable. A number of implicit solvent models have been developed to address this problem, many of which treat these two solvation effects separately...
March 20, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28317897/identification-of-mangiferin-as-a-potential-glucokinase-activator-by-structure-based-virtual-ligand-screening
#5
Qiuxia Min, Xinpei Cai, Weiguang Sun, Fei Gao, Zhimei Li, Qian Zhang, Luo-Sheng Wan, Hua Li, Jiachun Chen
The natural product mangiferin (compound 7) has been identified as a potential glucokinase activator by structure-based virtual ligand screening. It was proved by enzyme activation experiment and cell-based assays in vitro, with potency in micromolar range. Meanwhile, this compound showed good antihyperglycemic activity in db/db mice without obvious side effects such as excessive hypoglycaemia.
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317396/3d-qsar-studies-pharmacophore-modeling-and-virtual-screening-of-diarylpyrazole-benzenesulfonamide-derivatives-as-a-template-to-obtain-new-inhibitors-using-human-carbonic-anhydrase-ii-as-a-model-protein
#6
Yeganeh Entezari Heravi, Hassan Sereshti, Ali Akbar Saboury, Jahan Ghasemi, Marzieh Amirmostofian, Claudiu T Supuran
A 3D-QSAR modeling was performed on a series of diarylpyrazole-benzenesulfonamide derivatives acting as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The compounds were collected from two datasets with the same scaffold, and utilized as a template for a new pharmacophore model to screen the ZINC database of commercially available derivatives. The datasets were divided into training, test, and validation sets. As the first step, comparative molecular field analysis (CoMFA), CoMFA region focusing and comparative molecular similarity indices analysis (CoMSIA) in parallel with docking studies were applied to a set of 41 human (h) CA II inhibitors...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28316240/heme-gazing-illuminating-eukaryotic-heme-trafficking-dynamics-and-signaling-with-fluorescent-heme-sensors
#7
David A Hanna, Osiris Martinez-Guzman, Amit Ram Reddi
Heme (iron protoporphyrin IX) is an essential protein prosthetic group and signaling molecule required for most life on Earth. All heme dependent processes require the dynamic and rapid mobilization of heme from sites of synthesis or uptake to hemoproteins present in virtually every subcellular compartment. The cytotoxicity and hydrophobicity of heme necessitates that heme mobilization is carefully controlled to mitigate the deleterious effects of this essential toxin. Indeed, a number of disorders, including certain cancers, cardiovascular diseases, and aging and age-related neurodegenerative diseases, are tied to defects in heme homeostasis...
March 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28315995/ligand-based-virtual-screening-under-partial-shape-constraints
#8
Mathias M von Behren, Matthias Rarey
Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure...
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28306713/trypanocidal-effect-of-isotretinoin-through-the-inhibition-of-polyamine-and-amino-acid-transporters-in-trypanosoma-cruzi
#9
Chantal Reigada, Edward A Valera-Vera, Melisa Sayé, Andrea E Errasti, Carla C Avila, Mariana R Miranda, Claudio A Pereira
Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T...
March 17, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28303164/adverse-drug-reactions-triggered-by-the-common-hla-b-57-01-variant-a-molecular-docking-study
#10
George Van Den Driessche, Denis Fourches
BACKGROUND: Human leukocyte antigen (HLA) surface proteins are directly involved in idiosyncratic adverse drug reactions. Herein, we present a structure-based analysis of the common HLA-B*57:01 variant known to be responsible for several HLA-linked adverse effects such as the abacavir hypersensitivity syndrome. METHODS: First, we analyzed three X-ray crystal structures involving the HLA-B*57:01 protein variant, the anti-HIV drug abacavir, and different co-binding peptides present in the antigen-binding cleft...
2017: Journal of Cheminformatics
https://www.readbyqxmd.com/read/28302551/role-of-structural-bioinformatics-in-drug-discovery-by-computational-snp-analysis-a-proposed-protocol-for-analyzing-variation-at-the-protein-level
#11
REVIEW
David K Brown, Özlem Tastan Bishop
With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps toward an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as genome-wide association studies and candidate gene association studies. However, these statistical methods do not provide an understanding of the functional effects of variation...
March 13, 2017: Global Heart
https://www.readbyqxmd.com/read/28302310/design-synthesis-and-anti-diabetic-activity-of-triazolotriazine-derivatives-as-dipeptidyl-peptidase-4-dpp-4-inhibitors
#12
Bhumika D Patel, Shraddha V Bhadada, Manjunath D Ghate
Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model...
March 6, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28300596/combined-virtual-screening-mmpbsa-molecular-docking-and-dynamics-studies-against-deadly-anthrax-an-in-silico-effort-to-inhibit-bacillus-anthracis-nucleoside-hydrolase
#13
Masoumeh Karami, Chiya Jalali, Sako Mirzaie
Anthrax is a deadly disease caused by Bacillus anthracis, a dangerous biological warfare agent employed for both military and terrorist purposes. A critical selective target for chemotherapy against this disease is nucleoside hydrolase (NH), an enzyme still not found in mammals. In the current study, we have performed molecular docking and dynamics studies, aiming to propose the new potent inhibitors of B. anthracis NH among National Cancer Institute (NCI) Diversity Set. We also analyzed the principal interactions of proposed compounds with the active site residues of NH and the relevant factors to biological activity...
March 12, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28299742/virtual-high-throughput-screening-for-matrix-metalloproteinase-inhibitors
#14
Jun Yong Choi, Rita Fuerst
Structure-based virtual screening (SBVS) is a common method for the fast identification of hit structures at the beginning of a medicinal chemistry program in drug discovery. The SBVS, described in this manuscript, is focused on finding small molecule hits that can be further utilized as a starting point for the development of inhibitors of matrix metalloproteinase 13 (MMP-13) via structure-based molecular design. We intended to identify a set of structurally diverse hits, which occupy all subsites (S1'-S3', S2, and S3) centering the zinc containing binding site of MMP-13, by the virtual screening of a chemical library comprising more than ten million commercially available compounds...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28298429/speciation-network-in-laurasiatheria-retrophylogenomic-signals
#15
Liliya Doronina, Gennady Churakov, Andrej Kuritzin, Jingjing Shi, Robert Baertsch, Hiram Clawson, Juergen Schmitz
Rapid species radiation due to adaptive changes or occupation of new ecospaces challenges our understanding of ancestral speciation and the relationships of modern species. At the molecular level, rapid radiation with successive speciations over short time periods - too short to fix polymorphic alleles - is described as incomplete lineage sorting. Incomplete lineage sorting leads to random fixation of genetic markers and hence random signals of relationships in phylogenetic reconstructions. The situation is further complicated when you consider that the genome is a mosaic of ancestral and modern incompletely sorted sequence blocks that leads to reconstructed affiliations to one or the other relatives depending on the fixation of their shared ancestral polymorphic alleles...
March 15, 2017: Genome Research
https://www.readbyqxmd.com/read/28298118/quartic-scaling-mp2-for-solids-a-highly-parallelized-algorithm-in-the-plane-wave-basis
#16
Tobias Schäfer, Benjamin Ramberger, Georg Kresse
We present a low-complexity algorithm to calculate the correlation energy of periodic systems in second-order Møller-Plesset (MP2) perturbation theory. In contrast to previous approximation-free MP2 codes, our implementation possesses a quartic scaling, O(N(4)), with respect to the system size N and offers an almost ideal parallelization efficiency. The general issue that the correlation energy converges slowly with the number of basis functions is eased by an internal basis set extrapolation. The key concept to reduce the scaling is to eliminate all summations over virtual orbitals which can be elegantly achieved in the Laplace transformed MP2 formulation using plane wave basis sets and fast Fourier transforms...
March 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28294049/in-silico-analysis-of-amp-activated-protein-kinase-and-ligand-based-virtual-screening-for-identification-of-novel-ampk-activators
#17
Ammarah Ghaffar, Sidra Batool, Gohar Mushtaq, Muhammad Amjad Kamal
BACKGROUND: Adenosine-Monophosphate-Activated protein kinase (AMPK) is a conserved kinase that plays an important role in maintaining the homeostasis of cells. AMPK activation has a positive impact on treatment of diseases such as diabetes, obesity and cancer as well. This observation led to the development of AMPK activators. Certain naturally occurring compounds have also been known to activate AMPK. METHOD: In this study, we retrieved the AMPK activators that includes chemical drugs, xenobiotics and natural compounds and analyzed their interactions with AMPK via docking studies...
March 9, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28293633/combined-ligand-structure-based-virtual-screening-and-molecular-dynamics-simulations-of-steroidal-androgen-receptor-antagonists
#18
Yuwei Wang, Rui Han, Huimin Zhang, Hongli Liu, Jiazhong Li, Huanxiang Liu, Paola Gramatica
The antiandrogens, such as bicalutamide, targeting the androgen receptor (AR), are the main endocrine therapies for prostate cancer (PCa). But as drug resistance to antiandrogens emerges in advanced PCa, there presents a high medical need for exploitation of novel AR antagonists. In this work, the relationships between the molecular structures and antiandrogenic activities of a series of 7α-substituted dihydrotestosterone derivatives were investigated. The proposed MLR model obtained high predictive ability...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28291352/understanding-the-molecular-determinant-of-reversible-human-monoamine-oxidase-b-inhibitors-containing-2h-chromen-2-one-core-structure-based-and-ligand-based-derived-3-d-qsar-predictive-models
#19
Milan Mladenovic, Alexandros Patsilinakos, Adele Pirolli, Manuela Sabatino, Rino Ragno
Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including: (1) definition of optimized and validated structure-based (SB) 3-D QSAR models derived from available co-crystallized inhibitor-MAO B complexes; (2) elaboration of structure-activity relationships (SAR) features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rules assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro...
March 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28289374/discovery-of-compounds-that-positively-modulate-the-high-affinity-choline-transporter
#20
Parul Choudhary, Emma J Armstrong, Csilla C Jorgensen, Mary Piotrowski, Maria Barthmes, Rubben Torella, Sarah E Johnston, Yuya Maruyama, John S Janiszewski, R Ian Storer, Sarah E Skerratt, Caroline L Benn
Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene)...
2017: Frontiers in Molecular Neuroscience
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