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Marco Tutone, Anna Maria Almerico
The cyclin dependent kinases (CDKs) are a small family of serine/threonine protein kinases that can act as a potential therapeutic target in several proliferative diseases, including cancer. This short review is a survey on the more recent research progresses in the field achieved by using in silico methods. All the "armamentarium" available to the medicinal chemists (docking protocols and molecular dynamics, fragment-based, de novo design, virtual screening, and QSAR) has been employed to the discovery of new, potent, and selective inhibitors of cyclin dependent kinases...
August 4, 2017: European Journal of Medicinal Chemistry
Changho Jhin, Chu Won Nho, Keum Taek Hwang
The aim of this study was to develop quantitative structure-activity relationship (QSAR) models for predicting antioxidant activities of phenolic compounds. The bond dissociation energy of O-H bond (BDE) was calculated by semi-empirical quantum chemical methods. As a new parameter for QSAR models, sum of reciprocals of BDE of enol and phenol groups (X BDE ) was calculated. Significant correlations were observed between X BDE and antioxidant activities, and X BDE was introduced as a parameter for developing QSAR models...
August 11, 2017: Archives of Pharmacal Research
Ruifeng Liu, Mohamed Diwan M AbdulHameed, Anders Wallqvist
The quantitative structure-activity relationship (QSAR) approach has been used to model a wide range of chemical-induced biological responses. However, it had not been utilized to model chemical-induced genome-wide gene expression changes until very recently, owing to the complexity of training and evaluating a very large number of models. To address this issue, we examined the performance of a variable nearest neighbor (v-NN) method that uses information of near neighbors conforming to the principle that similar structures have similar activities...
August 10, 2017: Journal of Chemical Information and Modeling
Anacleto S de Souza, Marcelo T de Oliveira, Adriano D Andricopulo
Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0...
August 9, 2017: Journal of Computer-aided Molecular Design
Parthiban Marimuthu, Pavithra K Balasubramanian, Kalaimathy Singaravelu
The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently,molecular series of BenzothiazoleHydrazone(BH) inhibitorsthat exhibits drug-likenesscharacteristics,whichselectivelytargets Bcl-xLhave been reported.In the present study,dockingwas used toexplore the plausible binding mode of the highly active BH inhibitorwith Bcl-xL;and Molecular Dynamics(MD) simulation wasapplied toinvestigate the stability of predicted conformationover time...
August 10, 2017: Journal of Biomolecular Structure & Dynamics
Lauren P Wills
Toxicologists and chemical regulators depend on accurate and effective methods to evaluate and predict the toxicity of thousands of current and future compounds. Robust high-throughput screening (HTS) experiments have the potential to efficiently test large numbers of chemical compounds for effects on biological pathways. HTS assays can be utilized to examine chemical toxicity across multiple mechanisms of action, experimental models, concentrations, and lengths of exposure. Many agricultural, industrial, and pharmaceutical chemicals classified as harmful to human and environmental health exert their effects through the mechanism of mitochondrial toxicity...
August 5, 2017: Toxicology
Pervaiz Ali Channar, Aamer Saeed, Fayaz Ali Larik, Sajid Rashid, Qaiser Iqbal, Maryam Rozi, Saima Younis, Jamaluddin Mahar
Ten fused heterocyclic derivatives bearing the 2,6-di(subsituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as central rings were synthesized and structures of the compounds were established by analytical and spectral data using FTIR, EI-MS, (1)H NMR and (13)C NMR techniques. In vitro inhibitory activities of synthesized compounds on α-amylase, α-glucosidase and α-burylcholinesterase (α-BuChE) were evaluated using a purified enzyme assays. Compound 5c demonstrated strong and selective α-amylase inhibitory activity (IC50=1...
August 3, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mohammed Afzal Azam, Srikanth Jupudi
The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure-activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC50 values ranging from 0.18 to 663 μm. The best-fitted model showed a higher coefficient of determination (R(2) = 0...
October 2017: Journal of Receptor and Signal Transduction Research
Shikha Gupta, Nikita Basant
The rate constants of the hydroxyl radical reactions (kOH) with organic micropollutants (OMPs) in aqueous medium are important in designing the advanced oxidation processes (AOPs) for their removal. In this study, a quantitative structure-property relationship (QSPR) model for the prediction of kOH of diverse and emerging OMPs was developed in accordance with the OECD guidelines. A large experimental data set (n = 995) comprised of compounds with kOH values ranging from 7.9 × 10(5) to 6.8 × 10(10) M(-1) s(-1) was considered and several molecular descriptors were calculated...
October 2017: Chemosphere
Buge Yilmazer, Z Begum Yagci, Emre Bakar, Burcu Ozden, Kutlu Ulgen, Elif Ozkirimli
Beta-Glucocerebrosidase (GBA) is a lysosomal protein that is responsible for the hydrolysis of glycosylceramide into glucose and ceramide. Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease. Enzyme replacement therapies and substrate reduction methods that are used to treat Gaucher Disease fail when the disease is neuropathic because they fail to pass the blood brain barrier...
July 20, 2017: Journal of Molecular Graphics & Modelling
Yong Xie, Wei Peng, Fei Ding, Shu-Jie Liu, Hong-Juan Ma, Chang-Ling Liu
BACKGROUND: Agrochemicals have been crucial to the production of food, and the need for the development of novel agrochemicals continues unceasing owing to the loss of existing produces via the growth of resistance and the desire for products with more propitious environmental and toxicological patterns. RESULTS: The results of both CoMFA and CoMSIA models indicated that the biological activity can effectively be improved through the structural optimization and molecular design of these synthetic compounds from the aspects of steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields...
August 1, 2017: Pest Management Science
Styliani Fragki, Aldert H Piersma, Emiel Rorije, Marco J Zeilmaker
Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization...
July 28, 2017: Toxicology and Applied Pharmacology
Aude Kienzler, Mace G Barron, Scott E Belanger, Amy Beasley, Michelle R Embry
The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity dataset of 3488 chemicals, compare the approaches, and evaluate their utility and limitations in screening and early tier assessments...
July 31, 2017: Environmental Science & Technology
Pei H Luo, Xuan R Zhang, Lan Huang, Lun Yuan, Xang Z Zhou, X Gao, Ling S Li
NS2B-NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer's model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits...
July 31, 2017: Journal of Receptor and Signal Transduction Research
Li Wen, Qing Li, Wei Li, Qiao Cai, Yong-Ming Cai
Hydroxyl benzoic esters are preservative, being widely used in food, medicine, and cosmetics. To explore the relationship between the molecular structure and antibacterial activity of these compounds and predict the compounds with similar structures, Quantitative Structure-Activity Relationship (QSAR) models of 25 kinds of hydroxyl benzoic esters with the quantum chemical parameters and molecular connectivity indexes are built based on support vector machine (SVM) by using R language. The External Standard Deviation Error of Prediction (SDEPext), fitting correlation coefficient (R(2)), and leave-one-out cross-validation (Q(2)LOO) are used to value the reliability, stability, and predictive ability of models...
2017: Bioinorganic Chemistry and Applications
Olubukayo-Opeyemi Oyetayo, Oscar Méndez-Lucio, Andreas Bender, Hans Kiefer
pH shift-induced aggregation is frequently observed in downstream processing of monoclonal antibodies and has been shown to depend on solvent composition. To quantify the stabilizing effect of polyol additives against aggregation, we determined aggregation rate constants in the presence of a set of 14 compounds. Rate constants were then correlated with molecular descriptors in a quantitative structure activity relationship (QSAR) approach. The molecular size, volume, the charge, number of hydrogen acceptors, the stereochemistry and hydrophobicity of the compounds were identified as important descriptors...
July 25, 2017: International Journal of Pharmaceutics
E A Soliman, Siva S Panda, Marian N Aziz, ElSayed M Shalaby, Nawal Mishriky, Fahmy M Asaad, Adel S Girgis
Facile synthetic pathway for nicotinonitriles 5a‒o, 7a‒i was demonstrated through reaction of ketones 4a‒k, 6a‒f with ylidenemalononitrile 3 in the presence of sodium alkoxide. Meanwhile, nucleophilic attack of amines on 2-bromonicotinonitrile 9 (obtained through reaction of propenone 8 with malononitrile, followed by bromination with bromine in acetic acid) afforded 3-pyridinecarbonitriles 11a‒d. Single crystal X-ray of compound 7i reveals the monoclinic space group C2/c with 8 molecules per unit cell...
July 17, 2017: European Journal of Medicinal Chemistry
João Luiz Baldim, Bianca Gonçalves Vasconcelos de Alcântara, Olívia da Silva Domingos, Marisi Gomes Soares, Ivo Santana Caldas, Rômulo Dias Novaes, Tiago Branquinho Oliveira, João Henrique Ghilardi Lago, Daniela Aparecida Chagas-Paula
Flavonoids have demonstrated in vivo and in vitro leishmanicidal, trypanocidal, antioxidant, and prooxidant properties. The chemotherapy of trypanosomiasis and leishmaniasis lacks efficacy, presents high toxicity, and is related to the development of drug resistance. Thus, a series of 40 flavonoids were investigated with the purpose of correlating these properties via structure and activity analyses based on integrated networks and QSAR models. The classical groups for the antioxidant activity of flavonoids were combined in order to explain the influence of antioxidant and prooxidant activities on the antiparasitic properties...
2017: Oxidative Medicine and Cellular Longevity
Guanghui Zong, Xiaojing Yan, Jiawei Bi, Rui Jiang, Yinan Qin, Huizhu Yuan, Huizhe Lu, Yanhong Dong, Shuhui Jin, Jianjun Zhang
1,3,4-Thiadiazole and sugar-derived molecules have proven to be promising agrochemicals with growth promoting, insecticidal and fungicidal activities. In the research field of agricultural fungicide, applying union of active group we synthesized a new set of 1,3,4-thiadiazole xylofuranose derivatives and all of the compounds were characterized by 1H NMR and HRMS. In precise toxicity measurement, some of compounds exhibited more potent fungicidal activities than the most widely used commercial fungicide Chlorothalonil, promoting further research and development...
2017: PloS One
R Pravin Kumar, Naveen Kulkarni
Screening and selection tools to obtain focused libraries play a key role in successfully engineering enzymes of desired qualities. The quality of screening depends on efficient assays; however, a focused library generated with a priori information plays a major role in effectively identifying the right enzyme. As a proof of concept, for the first time, receptor dependent - 4D Quantitative Structure Activity Relationship (RD-4D-QSAR) has been implemented to predict kinetic properties of an enzyme. The novelty of this study is that the mutated enzymes also form a part of the training data set...
July 24, 2017: Scientific Reports
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