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Chemical Biology & Drug Design

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https://www.readbyqxmd.com/read/29450984/computational-studies-on-horseshoe-shape-pocket-of-human-orexin-receptor-type-2-and-boat-conformation-of-suvorexant-by-molecular-dynamics-simulations
#1
Qifeng Bai, Horacio Pérez-Sánchez, Zhuoyu Shi, Lanlan Li, Danfeng Shi, Huanxiang Liu, Xiaojun Yao
The FDA approved drug suvorexant binds to the horseshoe shape pocket of OX 2 R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX 2 R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX 2 R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX 2 R in complex with antagonist suvorexant are chosen to perform molecular dynamics (MD) simulations, QM/MM and MMGBSA calculations...
February 16, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29441688/-99m-tc-hynic-ser-3-j18-peptide-a-radiotracer-for-non-small-cell-lung-cancer-targeting
#2
Zahra Shaghaghi, Seyed Mohammad Abedi, Seyed Jalal Hosseinimehr
Radiolabeled peptide could be a useful tool for the diagnosis of non-small-cell lung cancer (NSCLC). In this study, HYNIC-(Ser)3-J18 peptide was labeled with99mTc using EDDA/tricine as co-ligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular specific binding and tumor targeting in A-549 cells and tumor bearing mice, respectively. The high radiochemical purity was obtained and this radiolabeled peptide exhibited high stability in buffer and serum. The radiolabeled peptide showed high affinity for the A-549 cells with a dissociation constant value (KD) of 4...
February 14, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29430875/novel-3-substituted-n-methylcarbazole-imidazolium-salt-derivatives-synthesis-and-cytotoxic-activity
#3
Yan-Hua Li, Zhou Bei, Yi-Min Shi, Yu-Peng Xun, Yun-Han Yang, Li-Juan Yang
A series of novel 3-substituted N-methylcarbazole-imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12). The results suggest that the presence of substituted 2-methyl-imidazole or imidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were important for improving cytotoxic activity. Compounds 17, 18, 27 and 28 with 4-bromophenacyl and naphthylacyl groups displayed good activities with IC50 values of 0...
February 11, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29415336/synthesis-and-evaluation-of-pyridinium-hydrazone-derivatives-as-potential-antitumoral-agents
#4
Sülünay Parlar, Yalçın Erzurumlu, Recep Ilhan, Petek Ballar Kırmızıbayrak, Vildan Alptüzün, Ercin Erciyas
The hydrazones of 4-hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF-7, PC3, U2OS and HEK293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems, showed high cytotoxic activity (IC50 = 3.27-8.54 μM) on cancer cells. 3d (4-(2-(4-hydroxybenzylidene)hydrazinyl)-1-(4-phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC50 value of 3...
February 7, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29415325/new-thiophene-acridine-compounds-synthesis-antileishmanial-activity-dna-binding-chemometric-and-molecular-docking-studies
#5
Vanessa de Lima Serafim, Mayara Barbalho Félix, Daiana Karla Frade Silva, Klinger Antônio da Franca Rodrigues, Patrícia Néris Andrade, Sinara Mônica Vitalino de Almeida, Sanderssonilo de Albuquerque Dos Santos, Jamerson Ferreira de Oliveira, Maria do Carmo Alves de Lima, Francisco Jaime Bezerra Mendonça-Junior, Marcus Tullius Scotti, Márcia Rosa de Oliveira, Ricardo Olímpio de Moura
In the present study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT01 and ACS01 -ACS07 ). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS01 and ACS02 derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC50 values of 9.60±3.19 and 10.95±3.96 μM. Additionally, these two derivatives were effective against antimony-resistant L...
February 7, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29405651/1-2-3-4-tetrahydroisoquinolines-as-inhibitors-of-hiv-1-integrase-and-human-ledgf-p75-interaction
#6
Anu George, Gopi Krishna Reddy Alavala, Satyanarayana Gedu, Raghavendra K Nidhanapati
Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes...
February 6, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29388345/a-novel-class-of-human-15-lox-1-inhibitors-based-on-3-hydroxycoumarin
#7
Seyed Jamal Alavi, Hamid Sadeghian, Seyed Mohammad Seyedi, Alireza Salimi, Hossein Eshghi
Inflammations, sensitivities, and some cancers in mammals are intimately linked to the activity of lipoxygenase enzymes. Owing to the importance of these enzymes, mechanistic studies, product analysis, and synthesis of inhibitors have expanded. In this study, a series of hydroxycoumarins, methoxy-3-hydroxy coumarins and 7-alkoxy-3-hydroxy coumarins were synthesized and evaluated as potential inhibitors of human 15-LOX-1. Among the synthetic coumarins, 7-methoxy-3-hydroxycoumarin (7-M3HC) derivative demonstrated potent inhibitory activity and the compound, 5f, showed the best result...
February 1, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29388326/discovery-of-novel-5-methyl-1h-pyrazole-derivatives-as-potential-anti-prostate-cancer-agents-design-synthesis-molecular-modeling-and-biological-evaluation
#8
Daoguang Zhang, Solomon Asnake, Jingya Zhang, Per-Erik Olsson, Guisen Zhao
Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide...
February 1, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29363274/in-silico-identification-synthesis-and-biological-evaluation-of-novel-tetrazole-inhibitors-of-murb
#9
Martina Hrast, Marko Jukič, Delphine Patin, Julie Tod, Christopher G Dowson, David I Roper, Hélène Barreteau, Stanislav Gobec
In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP-N-acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+ , a pharmacopohore model was generated and used in a virtual screening campaign with combined structure-based and ligand-based approaches...
January 24, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29363273/preparation-and-evaluation-of-effect-on-e-coli-and-s-aureus-of-radiolabeled-ampicillin-loaded-graphene-oxide-nanoflakes
#10
Fatma Yurt, Onur Alp Ersöz, Ersan Harputlu, Kasim Ocakoglu
Ampicillin is a one of effective antibiotics against Gram-positive and Gram-negative bacteria. The present study aims to label ampicillin loaded graphene oxide nanoflake (AMP-GO) with 99m Tc and evaluate of its in vitro binding to S. aureus and E. coli. Firstly, ampicillin was loaded onto graphene oxide nanoflake prepared. AMP-GO was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscope (SEM) techniques, and the amount of loaded ampicillin onto GO was determined by UV-Vis absorption spectroscopy...
January 24, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29345110/remarkable-similarity-in-plasmodium-falciparum-and-plasmodium-vivax-geranylgeranyl-diphosphate-synthase-ggpps-dynamics-and-its-implication-for-anti-malarial-drug-design
#11
Aishwarya Venkatramani, Clarisse G Ricci, Eric Oldfield, J Andrew McCammon
Malaria, mainly caused by Plasmodium falciparum and Plasmodium vivax, has been a growing cause of morbidity and mortality. P. falciparum is more lethal than is P. vivax, but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme involved in the biosynthesis of quinones and in protein prenylation, and has been proposed to be a malaria drug target. However, the structure of P. falciparum GGPPS (PfGGPPS) has not been determined, due to difficulties in crystallization...
January 18, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29336115/insight-into-the-inhibitor-discrimination-by-flt3-f691l
#12
Sharad Verma, Aditi Singh, Anchala Kumari, Bharati Pandey, Salma Jamal, Sukriti Goyal, Siddharth Sinha, Abhinav Grover
Fms-like tyrosine kinase 3 (FLT3) belongs to the receptor tyrosine kinase family and expressed in hematopoietic progenitor cells. FLT3 gene mutations are reported in ~30% of acute myeloid leukemia (AML) cases. FLT3 kinase domain mutation F691L is one of the common cause of acquired resistance to the FLT3 inhibitors including quizartinib. MZH29 and crenolanib were previously reported to inhibit FLT3 F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661and Asp829 were the most significant residues to target the FLT3 F691L which contribute most significantly to the binding energy with MZH29 and crenolanib...
January 16, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29316361/effects-of-serum-enzyme-thiol-and-forced-degradation-on-the-stabilities-of-%C3%AE-o-conotoxin-gexiva-1-2-and-gexiva-1-4
#13
Shurun Yu, Yong Wu, Pan Xu, Shuai Wang, Dongting Zhangsun, Sulan Luo
αO-conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC50 s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation, and thiol, which would be the key factors to affect stabilities of the two isomers in vivo...
January 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29316292/modulation-of-lateral-and-longitudinal-interdimeric-interactions-in-microtubule-models-by-laulimalide-and-peloruside-a-association-a-molecular-modeling-approach-on-the-mechanism-of-microtubule-stabilizing-agents
#14
Matías A Zúñiga, Joel B Alderete, Gonzalo A Jaña, Pedro A Fernandez, Maria J Ramos, Verónica A Jiménez
Laulimalide (LAU) and Peloruside A (PLA) are non-taxane microtubule stabilizing agents with promising antimitotic properties. These ligands promote the assembly of microtubules (MTs) by targeting a unique binding site on β-tubulin. The X-ray structure for LAU/PLA-tubulin association was recently elucidated but little information is available regarding the role of these ligands as modulators of interdimeric interactions across MTs. Herein we report the use of Molecular Dynamics (MD), Principal Component Analysis (PCA), MM/GBSA binding free energy calculations, and computational Alanine Scanning Mutagenesis (ASM) to examine effect of LAU/PLA association on lateral and longitudinal contacts between tubulin dimers in reduced MT models...
January 6, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29288534/an-overview-on-vadimezan-dmxaa-the-vascular-disrupting-agent
#15
REVIEW
Amir Daei Farshchi Adli, Rana Jahanban-Esfahlan, Khaled Seidi, Sonia Samandari-Rad, Nosratollah Zarghami
Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA(ASA404) or Vadimezan, a flavone-acetic acid-based drug is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however proposed direct and indirect mechanisms of action for DMXAA comprises: i) inducing apoptosis in endothelial cells; ii) hemorrhagic necrosis and ischemia in tumor; iii) release of serotonin (5-HT); vi) stimulation of innate immune system; v) production of inflammatory cytokines e...
December 30, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29266861/design-synthesis-and-antiprotozoal-evaluation-of-new-2-9-bis-substituted-aminomethyl-phenyl-1-10-phenanthroline-derivatives
#16
Jean Guillon, Anita Cohen, Rabindra Nath Das, Clotilde Boudot, Nassima Meriem Gueddouda, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Louise Basmaciyan, Camille Tisnerat, Sacha Mestanier, Sandra Rubio, Sophia Amaziane, Alexandra Dassonville-Klimpt, Nadine Azas, Bertrand Courtioux, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet
A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei).Biological results showed antiparasitic activity with IC50 values in the μM range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity...
December 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29266746/antibacterial-activities-and-molecular-mechanism-of-amino-terminal-fragments-from-pig-nematode-antimicrobial-peptide-cp-1
#17
Na Dong, Zhihua Wang, Shuli Chou, Licong Zhang, Anshan Shan, Junguang Jiang
High manufacturing costs and weak cell selectivity have limited the clinical application of naturally occurring peptides when faced with an outbreak of drug-resistance. To overcome these limitations, a set of antimicrobial peptides was synthesized with the general sequence of (WL)n, where n= 1, 2, 3 and WL was truncated from the N-terminus of Cecropin P1 without initial serine residues. The antimicrobial peptide WL3 exhibited stronger antimicrobial activity against both Gram-negative and Gram-positive microbes than the parental peptide CP-1...
December 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29251822/proteochemometric-modeling-of-the-origin-of-thymidylate-synthase-inhibition
#18
Behnam Rasti, S Shirin Shahangian
Due to its crucial role in DNA synthesis, thymidylate synthase (TS) has been considered as a potential therapeutic target. Inhibition of the enzyme is a promising strategy for the treatment of some hyper-proliferative diseases, including infections. Since TS species-specific inhibitors would be able to distinguish between the host and the pathogens, developing highly selective inhibitors is of great clinical importance. TS is among the most highly conserved enzymes over evolutionary history, making the design of its species-selective inhibitor significantly challenging...
December 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29251816/interaction-of-antivirals-with-a-heptameric-bundle-model-of-the-p7-protein-of-hepatitis-c-virus
#19
Sophie Dahl, Monoj Mon Kalita, Wolfgang B Fischer
A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock, MOE, LeadIT)...
December 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29250934/allo-a-tool-to-discriminate-and-prioritize-allosteric-pockets
#20
Rahmad Akbar, Volkhard Helms
Allosteric proteins make up a substantial proportion of human drug targets. Thus, rational design of small molecule binders that target these proteins requires the identification of putative allosteric pockets and an understanding of their potential activity. Here, we characterized allosteric pockets using a set of physicochemical descriptors and compared them to pockets that are found on the surface of a protein. Further, we trained predictive models capable of discriminating allosteric pockets from orthosteric pockets and models capable of prioritizing allosteric pockets in a set of pockets found on a given protein...
December 17, 2017: Chemical Biology & Drug Design
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