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ADME in silico

Bart I Roman, Rita C Guedes, Christian V Stevens, Alfonso T García-Sosa
In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of ( S )-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof...
2018: Frontiers in Chemistry
Maheshkumar R Borkar, Santosh Nandan, M N Harish Kumar, Jayashree Puttur, M Jisha, Dipankar Chatterji, Evans C Coutinho
BACKGROUND: The treatment of a bacterial infection when the bacterium is growing in a biofilm is a vexed issue. This is because the bacteria in a biofilm behaves differently compared to the individual planktonic free-form. As a result, traditional antibacterial agents lose their activity. OBJECTIVE: Presently, there are not many drugs that are effective against bacteria growing in biofilms. Based on literature reports, we have sought to develop novel derivatives of 4-hydroxy-2-pyridone as both antimycobacterial and antibiofilm agents...
May 24, 2018: Medicinal Chemistry
Mohamed A Abdelsalam, Omaima M AboulWafa, El-Sayed A M Badawey, Mai S El-Shoukrofy, Mostafa M El-Miligy, Noha Gouda, Mahmoud M Elaasser
BACKGROUND: Medicinal interest has focused on β-carbolines as anticancer agents. METHODOLOGY/RESULTS: Several β-carbolines were designed, synthesized and evaluated for their cytotoxic activity against MCF-7 and A-549 cancer cell lines using MTT assay. Compounds 13a, 13c, 13d and 20a were the most promising showing high selectivity indices. Compounds 13c and 20a showed potent inhibition of topoisomerase (topo-I) and kinesin spindle protein (KSP/Eg5 ATPase) which was confirmed by their docking results into the active site of both enzymes...
May 22, 2018: Future Medicinal Chemistry
Khaled F Greish, Loredana Salerno, Reem Al Zahrani, Emanuele Amata, Maria N Modica, Giuseppe Romeo, Agostino Marrazzo, Orazio Prezzavento, Valeria Sorrenti, Antonio Rescifina, Giuseppe Floresta, Sebastiano Intagliata, Valeria Pittalà
In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC50 values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket...
May 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jiangmei Wang, Yangyang Chen, Baoshi Liu, Qian Wang, Lulu Zhang, Zhenzhong Wang, Jun Zhou, Wei Xiao, Chunli Zheng, Yonghua Wang
ETHNOPHARMACOLOGICAL RELEVANCE: Cerebrovascular diseases (CBVDs), characterized by striking morbidity and mortality, have become the most common life-threatening diseases. The existing drugs of CBVDs target one or a few of pathogenic factors, the efficacy of which is limited because of the complexity of CBVDs. Traditional Chinese medicine (TCM), featured by multi-component and multi-target endows the great effectiveness in CBVDs treatment. For instance, Erigeron breviscapus (vant.) Hand...
May 18, 2018: Journal of Ethnopharmacology
Belgin Sever, Kaan Kucukoglu, Hayrunnisa Nadaroglu, Mehlika Dilek Altintop
BACKGROUND: Paraoxonase 1 (PON1) is a paraoxonase, arylesterase and lactonase associated with protection of lipoproteins and cell membranes against oxidative modification. OBJECTIVE: Based on antioxidative properties of PON1 and widely usage of 1,3,4-thiadiazole derivatives in pharmaceutical, agricultural, and materials chemistry, herein we aimed to evaluate PON1 activator potentials of 1,3,4-thiadiazole based compounds. METHOD: 2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio] acetophenone derivatives (1-18), previously synthesized by our research group, were in vitro evaluated for their activator effects on PON1 which was purified using ammonium sulfate precipitation (60-80%) and DEAE-Sephadex anion exchange chromatography...
May 17, 2018: Current Computer-aided Drug Design
Imran H Khan, Navin B Patel, Vatsal M Patel
BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene/2-thienylmethylene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-dione were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficient toward pathogen...
May 15, 2018: Current Computer-aided Drug Design
Mustafa Alhaji Isa, Rita Singh Majumdhar, Shazia Haider
The shikimate pathway is as an attractive target because it is present in bacteria, algae, fungi, and plants but does not occur in mammals. In Mycobacterium tuberculosis (MTB), the shikimate pathway is integral to the biosynthesis of naphthoquinones, menaquinones, and mycobactin. In these study, novel inhibitors of 3-dehydroquinate synthase (DHQS), an enzyme that catalyzes the second step of the shikimate pathway in MTB, were determined. 12,165 compounds were selected from two public databases through virtual screening and molecular docking analysis using PyRx 8...
May 11, 2018: Journal of Molecular Modeling
Laura De Luca, Stefania Ferro, Maria Rosa Buemi, Anna-Maria Monforte, Rosaria Gitto, Tanja Schirmeister, Louis Maes, Antonio Rescifina, Nicola Micale
Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug-resistance or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2-substituted-1H-benzo[d]imidazole derivatives (9a-d) showing affinity in the submicromolar range (Ki = 0...
May 4, 2018: Chemical Biology & Drug Design
Syeda Uroos Qazi, Shafiq Ur Rahman, Asia Naz Awan, Mariya Al-Rashida, Rima D Alharthy, Asnuzilawati Asari, Abdul Hameed, Jamshed Iqbal
A series of hydrazinecarboxamide derivatives were synthesized and examined against urease for their inhibitory activity. Among the series, the 1-(3-fluorobenzylidene)semicarbazide (4a) (IC50  = 0.52 ± 0.45 µM), 4u (IC50  = 1.23 ± 0.32 µM) and 4h (IC50  = 2.22 ± 0.32 µM) were found most potent. Furthermore, the molecular docking study was also performed to demonstrate the binding mode of the active hydrazinecarboxamide with the enzyme, urease. In order to estimate drug likeness of compounds, in silico ADME evaluation was carried out...
September 2018: Bioorganic Chemistry
Ashish D Patel, Rahul Barot, Inaxi Parmar, Ishan Panchal, Umang Shah, Mehul Patel, Bharat Mishtry
1,6-Dihydropyrimidine exerts notable pharmacological efficiency and emerged as integral backbones for treatment of type-II diabetes mellitus. To optimize the in vitro and in-silico study we carried out on substituted 1,6-Dihydropyrimidine. The objective of the present study is to evaluate the binding interaction of 1,6-Dihydropyrimidine compounds with protein tyrosine phosphatase (PTP1B) enzyme and also check ADME/T properties of best scored compounds. The in-silico study (docking) was carried out through target protein tyrosine phosphatase (PTP1B) retrieved from protein data bank having PDB ID: 2QBS and the anti diabetic activity of the test compounds was tested against protein tyrosine phosphatase (PTP1B) enzyme by using Calbiochem® PTP1B colorimetric assay kit...
April 26, 2018: Current Computer-aided Drug Design
Jinxiang Luo, Ting Lai, Tao Guo, Fei Chen, Linli Zhang, Wei Ding, Yongqiang Zhang
Thirty phenolic ether derivatives of scopoletin modified at the 7-hydroxy position were synthesized, and their structures were confirmed by IR, ¹H-NMR, 13 C-NMR, MS and elemental analysis. Preliminary acaricidal activities of these compounds against female adults of Tetranychus cinnabarinus (Boisduval) were evaluated using the slide-dip method. The results indicated that some of these compounds exhibit more pronounced acaricidal activity than scopoletin, especially compounds 32 , 20 , 28 , 27 and 8 which exhibited about 8...
April 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Priscila C B Halicki, Laís A Ferreira, Kelly C G De Moura, Paula F Carneiro, Karina P Del Rio, Tatiane Dos S C Carvalho, Maria do C F R Pinto, Pedro E A da Silva, Daniela F Ramos
Despite being a curable disease, tuberculosis (TB) remains a public health problem worldwide mainly due to lengthy treatment, as well as its toxic effects, TB/HIV co-infection and the emergence of resistant Mycobacterium tuberculosis strains. These barriers reinforcing the need for development of new antimicrobial agents, that ideally should reduce the time of treatment and be active against susceptible and resistant strains. Quinones are compounds found in natural sources and among them, the naphthoquinones show antifungal, antiparasitic, and antimycobacterial activity...
2018: Frontiers in Microbiology
Meenakshi Gupta, Kamal Kant, Ruchika Sharma, Anoop Kumar
INTRODUCTION: Parkinson's disease is affecting millions of people worldwide. The prevalence of Parkinson's disease is 0.3% globally, rising to 1% in more than 60 years of age and 4% in more than 80 years of age and the figures are thought to be doubled by 2030. Thus, there is a great need to identify novel therapeutic strategies or candidate drug molecule which can rescue neuronal degeneration. β-asarone has potential to act as a neuroprotective agent but regarding its role in Parkinson disease, very few reports are available...
April 16, 2018: Central Nervous System Agents in Medicinal Chemistry
Harun Patel, Rahul Pawara, Sanjay Surana
The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle...
March 29, 2018: Computational Biology and Chemistry
Ying Han, Bo Chen, Jingpu Zhang, Changqin Hu
Systems toxicology approaches have been used as important tools in the drug discovery and medicine quality control processes. The aim of this study was to assess the pharmacokinetic and toxicity properties of cephalosporins with an aminothiazoyl ring at the C-7 position (CATRs). Cardiac toxicity of the compounds was assessed in zebrafish embryos, and it was determined that CATRs disturbed the formation and development of the heart in a dose-dependent manner. Differentially expressed genes (DEGs) related to the heart were also identified by transcriptome analysis, and co-DEGs were obtained in the protein-protein interaction (PPI) network...
May 15, 2018: Toxicology and Applied Pharmacology
Gaurav Raj Dwivedi, Anupam Maurya, Dharmendra Kumar Yadav, Vigyasa Singh, Feroz Khan, Mahendra Kumar Gupta, Mastan Singh, Mahendra P Darokar, Santosh Kumar Srivastava
The emergence of multi drug resistance (MDR) in Gram-negative bacteria (GNB) and lack of novel classes of antibacterial agents have raised an immediate need to identify antibacterial agents, which can reverse the phenomenon of MDR. The purpose of present study was to evaluate synergy potential and understanding the drug resistance reversal mechanism of chanoclavine isolated from Ipomoea muricata against the multi-drug-resistant clinical isolate of Escherichia coli (MDREC). Although chanoclavine did not show antibacterial activity of its own, but in combination, it could reduce the minimum inhibitory concentration (MIC) of tetracycline (TET) up to 16-folds...
May 2, 2018: Journal of Biomolecular Structure & Dynamics
Rajendra H Patil, Firoz A Kalam Khan, Kaivalya Jadhav, Manoj Damale, Siddique Akber Ansari, Hamad M Alkahtani, Azmat Ali Khan, Shantanu D Shinde, Rajesh Patil, Jaiprakash N Sangshetti
We report the synthesis of some new piperazine-sulphonamide linked Schiff bases as fungal biofilm inhibitors with antibacterial and antifungal potential. The biofilm inhibition result of Candida albicans proposed that the compounds 6b (IC50  = 32.1 μM) and 6j (IC50  = 31.4 μM) showed higher inhibitory activity than the standard fluconazole (IC50  = 40 μM). Compound 6d (MIC = 26.1 μg/mL) with a chloro group at the para position was found to be the most active antibacterial agent of the series against Bacillus subtilis when compared with the standard ciprofloxacin (MIC = 50 μg/mL)...
April 2018: Archiv der Pharmazie
Rui Guo, Xiaoxiao Zhang, Jin Su, Haiyu Xu, Yanqiong Zhang, Fangbo Zhang, Defeng Li, Yi Zhang, Xuefeng Xiao, Shuangcheng Ma, Hongjun Yang
BACKGROUND: Quality marker (Q-markers) has been proposed as a novel concept for quality evaluation and standard elaboration of traditional Chinese medicine (TCM). Xin-Su-Ning capsule (XSNC) has been extensively used for the treatment of arrhythmia with the satisfactory therapeutic effects in clinics. However, it is lack of reliable and effective Q-markers of this prescription. PURPOSE: To identify potential Q-markers of XSNC against arrhythmia. STUDY DESIGN: An integrative pharmacology-based investigation was performed...
February 10, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Merve Ertas, Zafer Sahin, Barkin Berk, Leyla Yurttas, Sevde N Biltekin, Seref Demirayak
Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition...
April 2018: Archiv der Pharmazie
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