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Beata Żołnowska, Jarosław Sławiński, Zdzisław Brzozowski, Anna Kawiak, Mariusz Belka, Joanna Zielińska, Tomasz Bączek, Jarosław Chojnacki
A series of N -(aryl/heteroaryl)-4-(1 H -pyrrol-1-yl)benzenesulfonamides were synthesized from 4-amino- N -(aryl/heteroaryl)benzenesulfonamides and 2,5-dimethoxytetrahydrofuran. All the synthesized compounds were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. Compound 28 , bearing 8-quinolinyl moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 3, 5, and 7 µM, respectively. The apoptotic potential of the most active compound ( 28 ) was analyzed through various assays: phosphatidylserine translocation, cell cycle distribution, and caspase activation...
May 16, 2018: International Journal of Molecular Sciences
Marcos Lorca, Cesar Morales-Verdejo, David Vásquez-Velásquez, Juan Andrades-Lagos, Javier Campanini-Salinas, Jorge Soto-Delgado, Gonzalo Recabarren-Gajardo, Jaime Mella
The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques...
May 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Agha Zeeshan Mirza, Hina Shamshad
QSAR models as PLS, GFA, and 3D were developed for series of matriptase inhibitors using 35 piperidyl-cyclohexylurea compounds. The training and test sets were divided into a set of 28 and 8 compounds, respectively and the pki values of each compound were used in the analysis. Docking and alignment methodologies were used to develop models in 3D QSAR. The best models among all were selected on the basis of regression statistics as r2, predictive r2 and Friedman Lack of fit measure. Hydrogen donors and rotatable bonds were found to be positively correlated properties for this target...
May 16, 2018: Current Computer-aided Drug Design
Rucha R Wani, Hemchandra K Chaudhari
Docking and 3D QSAR studies were performed on Inhibitor of Bacterial DNA gyrase to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in PHASE; with a diverse set of 58 bacterial DNA gyrase inhibitors. A five point CPH with H-bond acceptor(A), Hydrophobic (H), Hydrogen bond Donor(D), Aromatic ring(R), a basic or positively ionizable feature. From them, the best pharmacophore hypothesis AAAPR gives a statistically significant and 3D QSAR model with 0.92 as R-squared value and 0...
May 15, 2018: Current Computer-aided Drug Design
Adewale J Ogunleye, Gabriel O Eniafe, Olumide K Inyang, Benjamin Adewumi, Olaposi I Omotuyi
Backgound: Inhibition of penicillin binding protein 2A (PBP2A) represents a sound drug design strategy in combatting Methicillin resistant Staphylococcus aureus (MRSA). Considering the urgent need for effective antimicrobials in combatting MRSA infections, we have developed a statistically robust ensemble of molecular descriptors (1, 2, & 3-D) from compounds targeting PBP2A in vivo. METHODS: 37 (training set: 26, test set: 11) PBP2A-inhibitors were submitted for descriptor generation after which an unsupervised, non-exhaustive genetic algorithm (GA) was deployed for fishing out the best descriptor subset...
May 15, 2018: Current Computer-aided Drug Design
Shahzaib Ahamad, Md Imtaiyaz Hassan, Neeraja Dwivedi
Tuberculosis (Tb) is an airborne infectious disease caused by Mycobacterium tuberculosis. Beta-carbonic anhydrase 1 ( β-CA1 ) has emerged as one of the potential targets for new antitubercular drug development. In this work, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulation approaches were performed on a series of natural and synthetic phenol-based β-CA1 inhibitors. The developed 3D-QSAR model ( r 2  = 0.94, q 2  = 0...
May 2018: 3 Biotech
Burak Tuzun, Sevtap Caglar Yavuz, Nazmiye Sabanci, Emin Saripinar
In the present work, pharmacophore identification and biological activity prediction for 86 pyrazole pyridine carboxylic acid derivatives were made using the electron conformational genetic algorithm approach which was introduced as a 4D-QSAR analysis by us in recent years. In the light of the data obtained from quantum chemical calculations at HF/6-311 G** level, the electron conformational matrices of congruity (ECMC) were constructed by EMRE software. Comparing the matrices, electron conformational submatrix of activity (ECSA, Pha) was revealed that are common for these compounds within a minimum tolerance...
May 13, 2018: Current Computer-aided Drug Design
Yahya Guzel, Ertugrul Aslan, Burcin Turkmenoglu, E Mesut Su
In this paper, we have introduced a new atomic descriptor with Klopman index to determine the local reactive sites of the molecular systems during electrophilic, nucleophilic attacks. This index, similar to other local reactivity descriptors but more advanced, has been used as a realistic descriptor to discover new aspects of molecular structure. Nonlinear least squares (NLLS) methods to define the parameters maximizing the fit between the observed points and the computed simulation results were performed according to the Levenberg-Marquardt (LM) algorithm...
May 13, 2018: Current Computer-aided Drug Design
Shivangi Agarwal, Ekta Verma, Vivek Kumar, Namrita Lall, Samaresh Sau, Arun K Iyer, Sushil K Kashaw
Tuberculosis is an infectious chronic disease caused by obligate pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Although many first and second line drugs are available for its treatment, but their irrational use has adversely lead to the emerging cases of multiple drug resistant and extensively drug-resistant tuberculosis. Therefore, there is an intense need to develop novel potent analogues for its treatment. This has prompted us to develop potent analogues against TB. The Mycobacterium tuberculosis genome provides us with number of validated targets to combat against TB...
May 3, 2018: Journal of Molecular Graphics & Modelling
Sutapa Mondal Roy
The quantum chemical descriptors based on density functional theory (DFT) are applied to predict the biological activity (log IC50 ) of one class of acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitors, viz. aminosulfonyl ureas. ACAT are very effective agents for reduction of triglyceride and cholesterol levels in human body. Successful two parameter quantitative structure-activity relationship (QSAR) models are developed with a combination of relevant global and local DFT based descriptors for prediction of biological activity of aminosulfonyl ureas...
April 27, 2018: Computational Biology and Chemistry
Yannan Li, Jing Ning, Yan Wang, Chao Wang, Chengpeng Sun, Xiaokui Huo, Zhenlong Yu, Lei Feng, Baojing Zhang, Xiangge Tian, Xiaochi Ma
The high risk of herb-drug interactions (HDIs) mediated by the herbal medicines and dietary supplements which containing abundant flavonoids had become more and more frequent in our daily life. In our study, the inhibition activities of 44 different structures of flavonoids toward human CYPs were systemically evaluated for the first time. According to our results, a remarkable structure-dependent inhibition behavior toward CYP3A4 was observed in vitro. Some flavonoids such as licoflavone (12) and irilone (30) exhibited the selective inhibition toward CYP3 A4 rather than other major human CYPs...
May 9, 2018: Toxicology Letters
Genyan Liu, Wenjie Wang, Youlan Wan, Xiulian Ju, Shuangxi Gu
Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0...
May 11, 2018: International Journal of Molecular Sciences
Hanrui Su, Chunyang Yu, Yongfeng Zhou, Lidong Gong, Qilin Li, Pedro J J Alvarez, Mingce Long
Tetra-amido macrocyclic ligand (TAML) activator is a functional analog of peroxidase enzymes, which activates hydrogen peroxide (H2 O2 ) to form high valence iron-oxo complexes that selectively degrade persistent aromatic organic contaminants (ACs) in water. Here, we develop quantitative structure-activity relationship (QSAR) models based on measured pseudo first-order kinetic rate coefficients (kobs ) of 29 ACs (e.g., phenols and pharmaceuticals) oxidized by TAML/H2 O2 at neutral and basic pH values to gain mechanistic insight on the selectivity and pH dependence of TAML/H2 O2 systems...
May 2, 2018: Water Research
Yu-Chen Lo, Stefano E Rensi, Wen Torng, Russ B Altman
Chemoinformatics is an established discipline focusing on extracting, processing and extrapolating meaningful data from chemical structures. With the rapid explosion of chemical 'big' data from HTS and combinatorial synthesis, machine learning has become an indispensable tool for drug designers to mine chemical information from large compound databases to design drugs with important biological properties. To process the chemical data, we first reviewed multiple processing layers in the chemoinformatics pipeline followed by the introduction of commonly used machine learning models in drug discovery and QSAR analysis...
May 8, 2018: Drug Discovery Today
Pavel Sidorov, Elisabeth Davioud-Charvet, Gilles Marcou, Dragos Horvath, Alexandre Varnek
This paper presents the effort of collecting and curating a data set of 15461 molecules tested against the malaria parasite, with robust activity and mode of action annotations. The set is compiled from in-house experimental data and the public ChEMBL database subsets. We illustrate the usefulness of the dataset by building QSAR models for antimalarial activity and QSPR models for modes of actions, as well as by the analysis of the chemical space with the Generative Topographic Mapping method. The GTM models perform well in prediction of both activity and mode of actions, on par with the classical SVM methods...
May 11, 2018: Molecular Informatics
S Andrade-Ochoa, J Correa-Basurto, L M Rodríguez-Valdez, L E Sánchez-Torres, B Nogueda-Torres, G V Nevárez-Moorillón
BACKGROUND: In order to develop new larvicidal agents derived from phytochemicals, the larvicidal activity of fifty molecules that are constituent of essential oils was evaluated against Culex quinquefasciatus Say. Terpenes, terpenoids and phenylpropanoids molecules were included in the in vitro evaluation, and QSAR models using genetic algorithms were built to identify molecular and structural properties of biological interest. Further, to obtain structural details on the possible mechanism of action, selected compounds were submitted to docking studies on sterol carrier protein-2 (SCP-2) as possible target...
May 10, 2018: Chemistry Central Journal
Ismail Daoud, Nadjib Melkemi, Toufik Salah, Said Ghalem
BACKGROUND AND PURPOSE: This work deals with several molecular modeling methods used to discover new therapeutic agents for treating the Alzheimer's disease (AD). The cholinergic hypothesis was initially presented over 30 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain. Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are of the keys targets of drugs for treating AD. METHODS: QSAR, Molecular Docking/Dynamics and ADME properties were carried out in order to study 36 compounds that belong to the 4-[(diethylamino)methyl]-phenol derivatives and test their AChE and BuChE inhibitory activities, MOE, HyperChem and others softwares were used to find the best compounds with high affinity...
March 29, 2018: Computational Biology and Chemistry
Parthiban Marimuthu, Kalaimathy Singaravelu
Myeloid cell leukemia 1 (Mcl1), is an anti-apoptotic member of the Bcl-2 family proteins, has gained considerable importance due to its overexpression activity prevents the oncogenic cells to undergo apoptosis. This overexpression activity of Mcl1 eventually develops strong resistance to a wide variety of anticancer agents. Therefore, designing novel inhibitors with potentials to elicit higher binding affinity and specificity to inhibit Mcl1 activity is of greater importance. Thus, Mcl1 acts as an attractive cancer target...
May 10, 2018: Journal of Biomolecular Structure & Dynamics
Amit Kumar Halder, Ana S Moura, M Natalia D S Cordeiro
Quantitative Structure-Activity Relationship (QSAR) models are becoming one of the most interesting fields for developing therapeutics and therapeutics related patents. At present, QSAR methodologies comprise a series of possibilities, including joining forces with machine learning methods and increasing even more the swiftness they might bring to the prospective development of therapeutics in the Health Sciences scope. Areas covered: After evaluating the period from 2010 to the end of 2018, the areas covered by the reviewed QSAR based therapeutics patents comprise three main fields (drug development, risk assessment and novel QSAR methodologies), and several areas, from cancer and cancer related symptomatology to neurodegenerative diseases, such as Parkinson's disease, or even monitoring several chemical particles carrier-mediums or interface frontiers...
May 10, 2018: Expert Opinion on Therapeutic Patents
Marcelo D Polêto, Victor H Rusu, Bruno I Grisci, Marcio Dorn, Roberto D Lins, Hugo Verli
The identification of lead compounds usually includes a step of chemical diversity generation. Its rationale may be supported by both qualitative (SAR) and quantitative (QSAR) approaches, offering models of the putative ligand-receptor interactions. In both scenarios, our understanding of which interactions functional groups can perform is mostly based on their chemical nature (such as electronegativity, volume, melting point, lipophilicity etc.) instead of their dynamics in aqueous, biological solutions (solvent accessibility, lifetime of hydrogen bonds, solvent structure etc...
2018: Frontiers in Pharmacology
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