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Julio Acuña, Jhoan Piermattey, Daneiva Caro, Sven Bannwitz, Luis Barrios, Jairo López, Yanet Ocampo, Ricardo Vivas-Reyes, Fabio Aristizábal, Ricardo Gaitán, Klaus Müller, Luis Franco
Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM)...
January 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Samina Kausar, Andre O Falcao
BACKGROUND: In-silico quantitative structure-activity relationship (QSAR) models based tools are widely used to screen huge databases of compounds in order to determine the biological properties of chemical molecules based on their chemical structure. With the passage of time, the exponentially growing amount of synthesized and known chemicals data demands computationally efficient automated QSAR modeling tools, available to researchers that may lack extensive knowledge of machine learning modeling...
January 16, 2018: Journal of Cheminformatics
Hiroshi Honda, Yurika Fujita, Toshio Kasamatsu, Anne Fuchs, Rolf Fautz, Osamu Morita
We have demonstrated that retrospective evaluation of existing data of in vitro chromosomal aberration test using the new cytotoxicity indices RICC (relative increase in cell count) or RPD (relative population doubling) reduces the false-positive rate. We have constructed an algorithm to predict the likelihood that past-positive results would differ when retested accordingly. Here, we emphasize the importance of reviewing existing in vitro chromosomal aberration test results. The present Letter not only supports the rediscovery of potentially useful chemicals excluded from further development as a result of misclassification due to in vitro false-positive results, but also contributes to the development of a precise Quantitative Structure-Activity Relationship (QSAR) model by providing an appropriate training data-set...
2018: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
Mark Howard Barley, Nicholas J Turner, Royston Goodacre
The ability to model the activity of a protein using Quantitative Structure Activity Relationships (QSAR) requires descriptors for the 20 naturally coded amino acids. In this work we show that by modifying some established descriptors we were able to model the activity data of 140 mutants of the enzyme epoxide hydrolase with improved accuracy. These new descriptors (referred to as Physical descriptors) also gave very good results when tested against a series of four dipeptide datasets. The Physical descriptors encode the amino acids using only two orthogonal scales: the first is strongly linked to hydrophillicity/hydrophobicity, and the second to the volume of the amino acid residue...
January 16, 2018: Journal of Chemical Information and Modeling
Davy Guan, Kevin Fan, Ian Spence, Slade Matthews
In vitro genotoxicity bioassays are cost-efficient methods of assessing potential carcinogens. However, many genotoxicity bioassays are inappropriate for detecting chemicals eliciting non-genotoxic mechanisms, such as tumour promotion, this necessitates the use of in vivo rodent carcinogenicity (IVRC) assays. In silico IVRC modelling could potentially address the low throughput and high cost of this assay. We aimed to develop and combine computational QSAR models of novel bioassays for the prediction of IVRC results and compare with existing software...
January 11, 2018: Regulatory Toxicology and Pharmacology: RTP
Manuela Sabatino, Dante Rotili, Alexandros Patsilinakos, Mariantonietta Forgione, Daniela Tomaselli, Fréderic Alby, Paola B Arimondo, Antonello Mai, Rino Ragno
Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis...
January 15, 2018: Journal of Computer-aided Molecular Design
Apilak Worachartcheewan, Alla P Toropova, Andrey A Toropov, Suphakit Siriwong, Jatupat Prapojanasomboon, Virapong Prachayasittikul, Chanin Nanatasenamat
BACKGROUND: Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS) that imposes a global health burden. Therefore, HIV therapeutic agents have been discovery and development. OBJECTIVE: To construct quantitative-structure activity relationship (QSAR) models of betulinic acid derivatives with anti-HIV activity using simplified molecular-input line-entry system (SMILES)-based descriptors Methods: A data set of 107 betulinic acid derivatives and their anti-HIV activity was used to develop QSAR models...
January 11, 2018: Current Computer-aided Drug Design
Parthiban Marimuthu, Yong-Jin Lee, Byung-Hoon Kim, Seong S Seo
Organophosphate compounds (OPC) have become the primary choice as insecticides and is widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that triggers a great challenge to public safety. Exposure of OPCs to human causes immediate excitation of cholinergic neurotransmission through transient elevation of synaptic acetylcholine (ACh) levels and accumulations. Likewise, prolonged exposure of OPCs can affect the processes in immune response, carbohydrate metabolism, cardiovascular toxicity and several others...
January 11, 2018: Journal of Biomolecular Structure & Dynamics
Iván J Montenegro, Soledad Del Corral, Georgina N Diaz Napal, María C Carpinella, Marco Mellado, Alejandro M Madrid, Joan Villena, Sara M Palacios, Mauricio A Cuellar
BACKGROUND: The antifeedant activity of 18 sesquiterpenoids of the drimane family (polygodial, drimenol and derivatives) was investigated. The results of this study against two insect species, Spodoptera frugiperda and Epilachna paenulata showed that polygodial, drimanic and nordrimanic derivatives exert antifeedant effects in these pests of agronomic interest indicating that they have potential as a biopesticide agent. RESULTS: Among the 18 compounds tested, the epoxynordrimane compound (11) and isonordrimenone (4) showed itself the highest activity (EC50 = 23...
January 8, 2018: Pest Management Science
Laura M Saavedra, Gustavo P Romanelli, Pablo R Duchowicz
BACKGROUND: We develop a QSAR model for predicting the larvicidal activity of 60 plant-derived molecules against Aedes aegypti L. (Diptera: Culicidae), vector of several diseases such as, dengue, yellow fever, chikungunya and Zika virus. The balanced subsets method (BSM) based on k-means cluster analysis (k-MCA) is employed to split the data set. The replacement method (RM) variable subset selection technique coupled with multivariable linear regression (MLR) proves to be successful for exploring 18,326 molecular descriptors and fingerprints calculated with PaDEL, Mold2 and EPI Suite open-source software...
January 4, 2018: Pest Management Science
Miao Yu, Qiong Gu, Jun Xu
PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits...
January 6, 2018: Journal of Computer-aided Molecular Design
Dali Wang, Xiaodan Wu, Zhifen Lin, Yangyang Ding
Antibiotics have become common pollutants in the environment. In most cases, the antibiotics in the environment exist as mixtures, posing joint effects on the organisms. Therefore, the mixture toxicity of the antibiotics can better reflect their environmental risks. In this paper, three types of commonly used antibiotics, i.e., sulfonamides (SAs), SA potentiators (SAPs) and tetracyclines (TCs) were investigated for their binary and tertiary mixture toxicity on three bacteria, Escherichia coli (E. coli), Vibrio fischeri (V...
January 3, 2018: Environmental Research
M Cristina Negritto, Clarissa Valdez, Jasmine Sharma, Christa Rosenberg, Cynthia R Selassie
Phenolic compounds and their derivatives are ubiquitous constituents of numerous synthetic and natural chemicals that exist in the environment. Their toxicity is mostly attributed to their hydrophobicity and/or the formation of free radicals. In a continuation of the study of phenolic toxicity in a systematic manner, we have examined the biological responses of Saccharomyces cerevisiae to a series of mostly monosubstituted phenols utilizing a quantitative structure-activity relationship (QSAR) approach. The biological end points included a growth assay that determines the levels of growth inhibition induced by the phenols as well as a yeast deletion (DEL) assay that assesses the ability of X-phenols to induce DNA damage or DNA breaks...
December 31, 2017: ACS Omega
Maria G Khrenova, Alexander V Nemukhin
The transient absorption spectroscopy of hydrolysis of the chromogenic substrate nitrocefin by the L1 metallo-β-lactamase (MβL), a bacterial enzyme responsible for destruction of β-lactam antibiotics molecules, showed formation and decay of a plausible red-shifted reaction intermediate. We propose a mechanism of this important reaction consistent with the transient kinetic data. Quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction pathway revealed occurrence of two reaction intermediates (I1, I2) between the enzyme-substrate (ES) and enzyme-product (EP) complexes...
January 3, 2018: Journal of Physical Chemistry. B
Stephen J Barigye, Matheus P Freitas, Priscila Ausina, Patricia Zancan, Mauro Sola-Penna, Juan Alberto Castillo-Garit
We have recently generalized the formerly alignment-dependent MIA-QSAR (acronym for Multivariate Image Analysis applied to Quantitative Structure Activity Relationships) method through the application of the Discrete Fourier Transform (DFT), allowing for its application to non-congruent and structurally diverse chemical compound datasets. Here, we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with the human aromatase inhibitory activity as the case study...
January 3, 2018: ACS Combinatorial Science
Kyoungyeul Lee, Minho Lee, Dongsup Kim
BACKGROUND: The identification of target molecules is important for understanding the mechanism of "target deconvolution" in phenotypic screening and "polypharmacology" of drugs. Because conventional methods of identifying targets require time and cost, in-silico target identification has been considered an alternative solution. One of the well-known in-silico methods of identifying targets involves structure activity relationships (SARs). SARs have advantages such as low computational cost and high feasibility; however, the data dependency in the SAR approach causes imbalance of active data and ambiguity of inactive data throughout targets...
December 28, 2017: BMC Bioinformatics
Radhika Ramachandran, Shanmughavel Piramanyagam
The C-X-C chemokine receptor type 4 receptor CXCR4 which acts as a co-receptor for human immunodeficiency virus-1, expressed in the later stages of infection is considered as an attractive and new target for drug design. Microbicides acting as co-receptor blockers are highly significant as these drugs block HIV lifecycle at early stage itself. The urgent need for a safe and effective microbicide urges to explore new CXCR4 antagonists which could be developed as microbicides. The pharmacophore based 3D-QSAR models and docking models were developed using PHASE and GLIDE modules of Schrodinger software...
September 2017: Virusdisease
Wensi He, Fangyou Yan, Qingzhu Jia, Shuqian Xia, Qiang Wang
The hazardous potential of ionic liquids (ILs) is becoming an issue of great concern due to their important role in many industrial fields as green agents. The mathematical model for the toxicological effects of ILs is useful for the risk assessment and design of environmentally benign ILs. The objective of this work is to develop QSAR models to describe the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of ILs against Staphylococcus aureus (S. aureus). A total of 169 and 101 ILs with MICs and MBCs, respectively, are used to obtain multiple linear regression models based on matrix norm indexes...
December 14, 2017: Chemosphere
Jiabing Wang, Di Yun, Jiali Yao, Weitao Fu, Fangyan Huang, Liping Chen, Tao Wei, Cuijuan Yu, Haineng Xu, Xiaoou Zhou, Yanqing Huang, Jianzhang Wu, Peihong Qiu, Wulan Li
Molecular hybridization is considered as an effective tactic to develop drugs for the treatment of cancer. A series of novel hybrid compounds of isatin and Michael acceptor were designed and synthesized on the basis of association principle. These hybrid compounds were tested for cytotoxic potential against human cancer cell lines namely, BGC-823, SGC-7901 and NCI-H460 by MTT assay. Most compounds showed good anti-growth activities in all tested human cancer cells. SAR and QSAR analysis may provide vital information for the future development of novel anti-cancer inhibitors...
December 18, 2017: European Journal of Medicinal Chemistry
Mohammad Amin Valizade Hasanloei, Razieh Sheikhpour, Mehdi Agha Sarram, Elnaz Sheikhpour, Hamdollah Sharifi
Quantitative structure-activity relationship (QSAR) is an effective computational technique for drug design that relates the chemical structures of compounds to their biological activities. Feature selection is an important step in QSAR based drug design to select the most relevant descriptors. One of the most popular feature selection methods for classification problems is Fisher score which aim is to minimize the within-class distance and maximize the between-class distance. In this study, the properties of Fisher criterion were extended for QSAR models to define the new distance metrics based on the continuous activity values of compounds with known activities...
December 26, 2017: Journal of Computer-aided Molecular Design
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