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Chemical Biology & Drug Design

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https://read.qxmd.com/read/30776195/design-synthesis-anti-mycobacterial-and-cytotoxic-evaluation-of-c-4-functionalized-1-8-naphthalimide-heterocyclic-hydrazide-conjugates
#1
Shalini, Matt D Johansen, Laurent Kremer, Vipan Kumar
This manuscript discloses the design and synthesis of a series of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates along with their anti-mycobacterial and cytotoxic evaluation. The present work assumes significance as it describes the first report on the amalgamation of C-4 substituted naphthalimides with various heterocyclic hydrazides. However, contrary to the rationale behind the synthesis of the conjugates, none of them inhibited the growth of Mycobacterium tuberculosis at the tested concentrations though these were non-cytotoxic towards the Vero kidney epithelial cell line...
February 18, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30776182/molecular-design-of-sequence-minimized-structure-optimized-and-hydrocarbon-stapled-helix-helix-interactions-in-the-trimer-of-hairpins-motif-of-pediatric-pneumonia-rsv-f-protein
#2
Jihong Wang, Jingxiu Zhang, Xiangguo Sun, Chengjun Liu, Xingli Li, Lei Chen
The respiratory syncytial virus fusion (RSV-F) protein is a primary target for vaccine and drug development against respiratory infection and pediatric pneumonia. The RSV-F core forms a trimer-of-hairpins (TOH) motif in post-fusion conformation, which is characterized by a six-helix bundle (6HB) where the three N-terminal HRn helices define a central coiled-coil, while three C-terminal HRc helices pack on the coiled-coil surface in an antiparallel manner. Here, one tightly packed HRn-HRc helix-helix interaction is stripped from the 6HB, which represents the minimum unit of RSV-F TOH motif...
February 18, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30773822/isolation-functional-characterization-and-biological-properties-of-mch-amp1-a-novel-antifungal-peptide-from-matricaria-chamomilla-l
#3
Sima Sadat Seyedjavadi, Soghra Khani, Hadi Zare-Zardini, Raheleh Halabian, Mehdi Goudarzi, Shohreh Khatami, Abbas Ali Imani Fooladi, Jafar Amani, Mehdi Razzaghi-Abyaneh
The antimicrobial activities of natural products have attracted much attention due to the increasing incidence of pathogens that have become resistant to drugs. Thus, it has been attempted to promisingly manage infectious diseases via a new group of therapeutic agents called antimicrobial peptides. In this study a novel antifungal peptide, MCh-AMP1, was purified by reverse phase-HPLC and sequenced by de novo sequencing and Edman degradation. The antifungal activity, safety, thermal and pH stability of MCh-AMP1 were determined...
February 18, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30737896/proteoliposome-based-model-for-screening-inhibitors-targeting-histidine-kinase-agrc
#4
Liying Zhang, Chunshan Quan, Xuning Zhang, Wen Xiong, Shengdi Fan
AgrC, as an integral membrane receptor protein with histidine kinase activity, is an important component of the agr quorum-sensing system of Staphylococcus aureus. AgrC acts as a sensor for the recognition of environmental signals and transduction of the signals into the cytoplasm. Therefore, AgrC is considered to be a compelling target for the development of novel quorum sensing inhibitors. Here, we constructed a proteoliposome-based model for screening inhibitors targeting AgrC by incorporating AgrC into liposomes...
February 8, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30721578/design-synthesis-and-evaluations-of-spiro-fused-benzoxaborin-derivatives-as-novel-boron-containing-compounds
#5
Itaru Natsutani, Riyo Iwata, Yu-Suke Yamai, Kyoji Ishida, Yasuo Nagaoka, Takaaki Sumiyoshi
Drug design using boron-containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron-containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro-fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro-fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs...
February 5, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30721576/a-high-quality-homology-model-for-the-human-dopamine-transporter-validated-for-drug-design-purposes
#6
Matthew C Castellana, Andrea Castellar Montes, Jon E Sprague, Tarek M Mahfouz
The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine-related therapies are in current development for individuals with dopamine-related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure activity relationship studies. Through structure based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs...
February 5, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30701670/spectrophotometric-versus-spectrofluorometric-assessment-in-the-study-of-the-relationships-between-lipid-peroxidation-and-metabolic-dysregulation
#7
Anca Ungurianu, Oana Șeremet, Daniela Grădinaru, Constantin Ionescu-Tîrgoviște, Denisa Margină, Rucsandra Dănciulescu Miulescu
Reactive oxygen species are crucial to normal cell function, but are also part of the pathogenesis of multiple modern maladies. As such, sensitive, fast, and reliable methods of appreciating redox status are needed. We aimed to optimize the Amplex Red (AR) and ferric-xylenol orange (FOX) methods using human serum samples, rat tissue homogenates, and mitochondrial preparations. For AR, we intended to reduce probe concentration, maintaining method sensitivity, as well as extending its use from isolated lipoproteins samples, and readjust it for a high-throughput application...
January 30, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30697932/spotlight-on-17-aag-as-an-hsp90-inhibitor-for-molecular-targeted-cancer-treatment
#8
REVIEW
Sona Talaei, Hassan Mellatyar, Asadollah Asadi, Abolfazl Akbarzadeh, Roghayeh Sheervalilou, Nosratollah Zarghami
Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins...
January 29, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30693676/bennett-acceptance-ratio-method-to-calculate-the-binding-free-energy-of-bace1-inhibitors-theoretical-model-and-design-of-new-ligands-of-the-enzyme
#9
Margarita Gutiérrez, Gabriel A Vallejos, Magdalena P Cortés, Carlos Bustos
In recent years, the design, development, and evaluation of several inhibitors of the BACE1 enzyme, as part of Alzheimer's treatment, have gathered the scientific community's interest. Here, a linear regression model was built using binding free energy calculations through the Bennett acceptance ratio method for 20 known inhibitors of the BACE1 enzyme, with a Pearson coefficient of R = 0.88 and R2  = 0.78. The validation of this model was verified employing eight additional random inhibitors, which also gave a linear correlation with R = 0...
January 29, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30689282/exploring-binding-mechanisms-of-vegfr2-with-three-drugs-lenvatinib-sorafenib-and-sunitinib-by-molecular-dynamics-simulation-and-free-energy-calculation
#10
Yu Wang, Cheng Peng, Guimin Wang, Zhijian Xu, Yongfeng Luo, Jinan Wang, Weiliang Zhu
Lenvatinib (LEN), sorafenib (SOR) and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG-in and DFG-out state, respectively. SUN binds to the DFG-out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2-drugs systems...
January 28, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30689273/synthesis-and-antitumor-activity-of-2-isocamphanyl-thiosemicarbazone-derivatives-via-ros-enhanced-mitochondria-damage
#11
Yunyun Wang, Zhonglong Wang, Hongbo Kuang, Yan Zhang, Wen Gu, Yongqiang Zhu, Shifa Wang
A series of novel 2-isocamphanyl thiosemicarbazone derivatives were synthesized and characterized by 1 H NMR, 13 C NMR and HRMS. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against four cancer cell lines (RPMI-8226, A549, MDA-MB-231 and HepG2 cancer cells) and showed low toxicity against human gastric mucosal cells (GES-1). Among them, compound 4h exhibited excellent antitumor activity against the tested cancer cells with IC50 values of 0.4, 1.1, 1.6, and 1.7 μM for MDA-MB-231, RPMI-8226, A549 and HepG2, respectively...
January 28, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30688405/a-combined-drug-discovery-strategy-based-on-machine-learning-and-molecular-docking
#12
Yanmin Zhang, Yuchen Wang, Weineng Zhou, Yuanrong Fan, Junnan Zhao, Lu Zhu, Shuai Lu, Tao Lu, Yadong Chen, Haichun Liu
Data mining methods based on machine learning play an increasingly important role in drug design and discovery. In the current work, eight machine learning methods including decision trees, k-Nearest neighbor, support vector machines, random forests, extremely randomized trees, AdaBoost, gradient boosting trees, and XGBoost were evaluated comprehensively through a case study of ACC inhibitor data sets. Internal and external data sets were employed for cross-validation of the eight machine learning methods. Results showed that the extremely randomized trees model performed best and was adopted as the first step of virtual screening...
January 28, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30667602/identification-of-nek3-and-mok-as-novel-targets-for-lithium
#13
LETTER
Ana Bravo, Héctor de Lucio, Pedro A Sánchez-Murcia, Antonio Jiménez-Ruiz, Paula M Petrone, Federico Gago, Alvaro Cortés Cabrera
Lithium ion, commonly used as the carbonate salt in the treatment of bipolar disorders, has been identified as an inhibitor of several kinases, including Glycogen Synthase Kinase-3β, for almost 20 years. However, both the exact mechanism of enzymatic inhibition and its apparent specificity for certain metalloenzymes are still a matter of debate. A data-driven hypothesis is presented that accounts for the specificity profile of kinase inhibition by lithium in terms of the presence of a unique protein environment in the magnesium binding site...
January 22, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30667164/design-synthesis-and-biological-evaluation-of-4-aminopyrimidine-or-4-6-diaminopyrimidine-derivatives-as-beta-amyloid-cleaving-enzyme-1-bace1-inhibitors
#14
Xiufeng Xu, Peng Lü, Junjie Wang, Fengrong Xu, Lei Liang, Chao Wang, Yan Niu, Ping Xu
A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC50 = 37.4 μM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC50 = 1.4 μM), was 26-fold greater than that of 1 based on a fluorescence resonance energy transfer (FRET) assay, and a parallel artificial membrane permeability assay (PAMPA) suggested that it could pass through the blood-brain barrier (BBB)...
January 22, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30667160/combined-comparative-molecular-field-analysis-comfa-comparative-molecular-similarity-indices-analysis-comsia-molecular-docking-and-molecular-dynamics-studies-of-histone-deacetylase-6-hdac6-inhibitors
#15
Monika Sharma, Prakash Jha, Priyanka Verma, Madhu Chopra
Human histone deacetylase isoform 6 (HDAC6) has been shown to have an immense role in cell motility and aggresome formation and is being an attractive selective target for the treatment of multiple tumour types and neuro-degenerative conditions. The discovery of selective HDAC6 inhibitors with new chemical functionalities is therefore of utmost interest to researchers. In order to examine the structural requirements for HDAC6 specific inhibitors and to derive predictive model which can be used for designing new selective HDAC6 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) study was carried out on a diverse set of ligands using common feature-based pharmacophore alignment followed by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques...
January 22, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30663249/plasmodium-falciparum-multi-drug-resistance
#16
REVIEW
Subhashree Rout, Rajani Kanta Mahapatra
Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential anti-malarial drug. The major classes of approved anti-malarial drugs that are governed as first-line treatment in tropical and sub-tropical areas include quinolines, naphthoquinones, antifolates, 8-aminoquinolines, and endoperoxides...
January 20, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30657643/design-synthesis-and-evaluation-of-a-series-of-novel-phenylpropanoic-acid-derivatives-agonists-for-the-ffa1
#17
Jiaju Yang, Enke Gu, Ting Yan, Daoming Shen, Bainian Feng, Chunlei Tang
Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837 and LY2881835. Among them, most promising compounds 7, 14 and 15 were obtained with EC50 values of 82, 79 and 88 nM, exhibiting a powerful agonistic activity compared to TAK-875(95...
January 18, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30637990/bisubstrate-inhibitors-to-target-histone-acetyltransferase-1-hat1
#18
Liza Ngo, Tyler Brown, Y George Zheng
Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid-1990s; however, it remains one of the poorly studied enzymes in comparison to the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here we designed a set of peptide-CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency...
January 14, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30637977/computational-insights-into-the-different-catalytic-activities-of-cyp3a4-and-cyp3a5-towards-schisantherin-e
#19
Yuhan Xue, Junhao Li, Zengrui Wu, Guixia Liu, Yun Tang, Weihua Li
The cytochrome CYP3A4 and CYP3A5 share 84% sequence identity, but they exhibit different catalytic activities towards some substrates. Schisantherin E (SE) was recently identified as a selective substrate of CYP3A5, which exhibited catalytic efficiency that was more than 23 times higher than CYP3A4. At present, however, the structural determinants responsible for the different catalytic activities of the two enzymes towards SE have not been fully understood. In this study, a combination of molecular docking, molecular dynamic simulations, and binding free energy calculation was performed on the CYP3A4/CYP3A5-SE systems to investigate the issue...
January 14, 2019: Chemical Biology & Drug Design
https://read.qxmd.com/read/30637976/anti-cancer-effects-of-cqbto-a-chloroquine-and-benzo-e-triazine-oxide-conjugate
#20
Ziyang Guo, Hailong Pei, Jing Nie, Wentao Hu, Jian Zhang, Jiahan Ding, Shuxian Pan, Bingyan Li, Tom K Hei, Weiqiang Chen, Guangming Zhou
AIM: Autophagy is a self-protective process, and it confers cancer cells resistance against radio-chemotherapeutics. To induce cancer cell death, a series of compounds of 3- ((4-((7-chloroquinolin-4-yl)amino)butyl)amino)- 7-substituted benzo[e][1,2,4] triazine 1-oxide or CQBTO containing two critical chemical groups were designed and synthesized. One compound, BTO, yielded free radicals to trigger autophagy, and the other one, chloroquine (CQ), was an inhibitor of autophagy. We hypothesized that the compounds could kill cancer cells effectively by inducing incomplete autophagy...
January 13, 2019: Chemical Biology & Drug Design
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