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Chemical Biology & Drug Design

Bo Fan, Yunfei Li, Bi Yong, Ling Tong, Dongxiang Li, Yi Wang
In recent years, multi-component therapies are increasingly utilized to treat complex diseases such as cancer, diabetes, and other chronic complex diseases. Here, we proposed the protocol for rational design of drug combination with poly-pharmacological effects by integration of design of experiments (DOE), computational modeling and multiple-objective optimization algorithm. Here we introduce a common workflow for modeling quantitative relationship of chemical composition and multiple activities of drug combinations...
September 19, 2018: Chemical Biology & Drug Design
Aussara Panya, Petlada Yongpitakwattana, Prapaphan Budchart, Nunghathai Sawasdee, Sucheewin Krobthong, Atchara Paemanee, Sittiruk Roytrakul, Siriluk Rattanabunyong, Kiattawee Choowongkomon, Pa-Thai Yenchitsomanus
The therapeutic activities of food-derived bioactive proteins and peptides are attracting increased attention within the research community. Medicinal plants used in traditional medicines are an excellent source of bioactive proteins and peptides, especially those traditionally prepared by water extraction for use as tea or food supplement. In this study, novel bioactive peptides were isolated from enzymatic digests of 33 Thai medicinal plants. The inhibitory activity of each against dengue virus (DENV) infection was investigated...
September 17, 2018: Chemical Biology & Drug Design
Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen
Recently, bromodomain containing protein 9 (BRD9), 7 (BRD7) and 4 (BRD4) have been potential target of anti-cancer drug design. Molecular dynamic (MD) simulations followed by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculation were performed to study the selective mechanism of I-BRD9 inhibitor H1B and its derivatives N1D, TVU and 5V2 toward BRD9 and BRD4. The rank of our calculated binding free energies agrees with that of the experimental data. The results show that binding free energy of H1B to BRD7 is slightly lower than that of H1B to BRD9, and all four inhibitors bind more tightly to BRD9 than to BRD4...
September 17, 2018: Chemical Biology & Drug Design
Yuzhen Niu, Yan Zhang, Xiaojun Yao
BRAF kinase is an essential target for anti-cancer drug development. Emergence of the β3-αC loop deletion mutation (ΔNVTAP) in BRAF kinase frequently occurred in human cancers seriously compromises the therapeutic efficacy of some BRAF kinase inhibitors, such as dabrafenib and vemurafenib. However, the mechanism of this resistance is still not well-understood. In this study, the influence of the β3-αC deletion mutation on the binding profiles of three BRAF kinase inhibitors (AZ628, dabrafenib and vemurafenib) with BRAFV 600E or BRAFΔ NVTAP was explored by conventional molecular dynamics (MD) simulations and binding free energy calculations...
September 17, 2018: Chemical Biology & Drug Design
Ning Sun, Dongli Li, Jinqiang Hou, Wei Long, Qi Guo, Yujing Lu, Kun Zhang, Wenchang Yuan, Wing-Leung Wong
A new propeller-like small molecule was synthesized with three terminal amino side groups. The molecule was found to be a selective nucleic acid binder towards telo21 G-quadruplex DNA compared with other representative nucleic acids including single-stranded DNA (dA21), duplex DNA (ds26), and RNA. The fluorescent signal of the molecule upon interaction with telo21 G-quadruplex structure shows remarkable enhancement (Fmax /F0 = 17.9) while interaction with other nucleic acids the signal enhancement is less than 2...
September 14, 2018: Chemical Biology & Drug Design
Daniel Conole, Samuel H Myers, Filipa Mota, Adrian J Hobbs, David L Selwood
Endothelium-derived C-type natriuretic peptide possesses cytoprotective and anti-atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C-type natriuretic peptide are somewhat mediated by the natriuretic peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimised an array of biophysical methods including surface plasmon resonance, fluorescence polarisation and thermal shift assays to aid in the design, assessment and characterisation of small molecule agonist interactions with natriuretic peptide receptors...
September 14, 2018: Chemical Biology & Drug Design
Xian H Wang, Mei Huang, Chang K Zhao, Chan Li, Lang Xu
Three components of Camptothecin, hydroxyacetic acid and functionalized norcantharidins were constructed together to form a novel series of camptothecin derivatives in a good yield. The synthesized campthothecin-HAA-norcantharidin conjugate pro-drugs could suppress cancer cell growth in vitro. These conjugated pro-drug molecules possess therapeutic potential as novel bi-functional conjugates platforms for cancer treatment. This article is protected by copyright. All rights reserved.
September 14, 2018: Chemical Biology & Drug Design
Edson Roberto da Silva, Simone Brogi, Alessandro Grillo, Giuseppe Campiani, Sandra Gemma, Paulo Cezar Vieira, Claudia do Carmo Maquiaveli
This study describes the activity of five natural hydroxycinnamic acids and derived compound: caffeic (1), rosmarinic (2), chlorogenic (3) and cryptochlorogenic (4) acids and isoverbascoside (5). All compounds inhibited Leishmania amazonensis arginase with IC50 in range of 1.5 - 11 μM. Compound 2 and 5 also showed activity against promastigotes of L. amazonensis with IC50 = 61 (28-133) μM and IC50 = 14 (9-24) μM, respectively. Further computational studies applying molecular docking simulations were performed on the competitive inhibitors to gain insight into the molecular basis for arginase inhibition and could be exploited to the development of new antileishmanials drug targeting parasite arginase...
September 14, 2018: Chemical Biology & Drug Design
Naeem-Ul-Haq Khan, Syed Ali Raza Naqvi, Samina Roohi, Tauqir A Sherazi, Zulfiqar Ali Khan, Ameer Fawad Zahoor
The development of functional imaging is a promising strategy for diagnosis and treatment of infectious and cancerous diseases. In this study epirubicin was developed as a [99m Tc]-labeled radiopharmaceutical for the imaging of multi-drug resistant S. aureus infections. The labeling was carried out using sodium pertechnetate (Na99m TcO4 ; ~370 MBq). The other parameters such as amount of ligand, reducing agent (SnCl2 .2H2 O) and pH were optimized. The highest labeling yield ≥96.98% was achieved when 0.3 mg epirubicin, 13 μg SnCl2 ...
September 14, 2018: Chemical Biology & Drug Design
Romina J Ronchi, Claire Beaufay, Joanne Bero, Juan B Robirosa, Marcia Mazzuca, Jorge A Palermo, Joëlle Quetin-Leclercq, Marianela Sánchez
In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 μM, with selectivity indices > 10, and low antiplasmodial effects with IC50 >29 μM...
September 14, 2018: Chemical Biology & Drug Design
Hui Li Heng, Chin Fei Chee, Chun Keng Thy, Jia Ti Tee, Sek Peng Chin, Deron R Herr, Michael J C Buckle, Ian C Paterson, Stephen W Doughty, Noorsaadah Abd Rahman, Lip Yong Chung
Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system (CNS) disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesised and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb = 8...
September 14, 2018: Chemical Biology & Drug Design
Muhammed Tilahun Muhammed, Esin Aki-Yalcin
Homology modeling is one of the computational structure prediction methods that are used to determine protein 3D structure from its amino acid sequence. It is considered to be the most accurate of the computational structure prediction methods. It consists of multiple steps that are straightforward and easy to apply. There are many tools and servers that are used for homology modeling. There is no single modeling program or server which is superior in every aspect to others. Since the functionality of the model depends on the quality of the generated protein 3D structure, maximizing the quality of homology modeling is crucial...
September 6, 2018: Chemical Biology & Drug Design
Michelle Fidelis Corrêa, Álefe Jhonatas Ramos Barbosa, Gustavo Ariel Borges Fernandes, Jillian G Baker, João Paulo Dos Santos Fernandes
Histamine is a transmitter that activates the four receptors H1 R to H4 R. The H3 R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1-(2,3-dihydro-1-benzofuran-2-yl)methylpiperazines (LINS01 compounds) have the selectivity for the H3 R over the H4 R. Here, we describe their pharmacological properties at the human H1 R and H2 R in parallel with the H3 R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays...
August 28, 2018: Chemical Biology & Drug Design
Mihir Khambete, Harish Kundaikar, Archana Raju, Sachin Lonkar, Mariam Degani, Mukti Kanta Ray
We report the design-synthesis of several nitrothiophene containing molecules as antituberculosis agents. The molecules were designed on the basis of previously reported nitrofuran molecules in our laboratory and the α,β-unsaturated linker was modified to cyclized linker in order to overcome the challenge of low solubility and possible toxicity. The stereoelectronic properties such as HOMO, LUMO and HOMO-LUMO gap (HLG) along with other properties such as aqueous solvation energies and QPLogS values were studied...
August 24, 2018: Chemical Biology & Drug Design
Ying Zhou, Xiaoyun Zhu, Leilei Zhang, Chunlei Tang, Bainian Feng
This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC50 values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high-fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development...
August 18, 2018: Chemical Biology & Drug Design
Hossein Aghazadeh, Hamed Memariani, Reza Ranjbar, Kamran Pooshang Bagheri
Human cathelicidin LL-37 has recently attracted interest as a potential therapeutic agent, mostly because of its ability to kill a wide variety of pathogens and cancer cells. In this study, we aimed to investigate the antibacterial activity and cytotoxicity of previously designed LL-37 anticancer derivatives (i.e. P7, P22, and P38). Calcein release assay and field emission-scanning electron microscopy (FE-SEM) were performed to elucidate the possible mechanism of action of P38, the peptide with the highest bactericidal activity...
August 18, 2018: Chemical Biology & Drug Design
Sidharth S Kar, Varadaraj G Bhat, Vishnu P Shenoy, Indira Bairy, G Gautham Shenoy
In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives (5a-f, 6a-f) were designed and synthesized. The representative compounds showed promising in vitro activity against drug susceptible, isoniazid resistant and multi drug resistant strains of Mycobacterium tuberculosis with MIC values of 1.56 μg/mL (6b), 6.25 μg/mL (6a-d) and 3.125 μg/mL (6b-c) respectively. All the synthesized compounds exhibited satisfactory safety profile (CC50 > 300 μg/mL) against Vero and HepG2 cells...
August 17, 2018: Chemical Biology & Drug Design
Antonio Romo-Mancillas, Roselyn Lemus, Raúl Pérez-Estrada, Francisco Kuribreña-Romero de Terreros, Lenin Domínguez-Ramírez
Calpains are cysteine proteases involved in the development of several human chronic illnesses such as neurodegenerative diseases, cardiovascular ailments, diabetes and obesity which constitutes them into possible therapeutic targets. Here, using molecular dynamic simulations and docking, we studied the binding of known inhibitors to representative members of classical and non-classical calpains. Our aim is to gain better understanding on the inhibition mechanism of calpains and to develop better and more specific inhibitors...
August 14, 2018: Chemical Biology & Drug Design
Ying Huang, Hui Xiao, Yaxiong Liu, Jiaming Gan, Quanhong Yan
In this study, HPLC-MS/MS with triple-quadrupole tandem mass spectrometer was used to analyze the base-catalyzed thermal degradation derivative of progesterone in Chinese Pharmacopoeia. The full-scan spectrometry revealed that the degradation product was an isomer of progesterone, it was proposed as impurity M ((17α)-pregn-4-ene-3,20-dione) in European Pharmacopoeia, and both the derivative and progesterone were neutral molecules. Four kinds of chromatographic column characterization databases including PQRI database using Snyder/Dolan method, the USP chromatographic column database using the SRM 870 tests, the Tanaka/Euerby approach within the ACD program, and the Hoogmartens approach were compared...
August 14, 2018: Chemical Biology & Drug Design
Giovinna Arfan, Chu Yang Fann Ong, Siew Mei Samantha Ng, Qiu Ying Lau, Fui Mee Ng, Esther Hong Qian Ong, Jeffrey Hill, Cheng San Brian Chia
Staphylococcus aureus is the pathogen responsible for the majority of human skin infections. In particular, the methicillin-resistant variety, MRSA, has become a global clinical concern. The extensive use of mupirocin, the first-line topical antibacterial drug of choice, has led to the emergence of mupirocin-resistant MRSA globally, resulting in the urgent need for a replacement. Antimicrobial peptides are deemed plausible candidates. Herein, we describe a structure-activity relationship approach in the design of an ultra-short peptide with potent anti-MRSA activity with a rapid, bactericidal mode of action...
August 13, 2018: Chemical Biology & Drug Design
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