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Jonathan D Tyzack, Laurent Fernando, Antonio J M Ribeiro, Neera Borkakoti, Janet M Thornton
There are numerous applications that use the structures of protein-ligand complexes from the PDB, such as 3D pharmacophore identification, virtual screening, and fragment-based drug design. The structures underlying these applications are potentially much more informative if they contain biologically relevant bound ligands, with high similarity to the cognate ligands. We present a study of ligand-enzyme complexes that compares the similarity of bound and cognate ligands, enabling the best matches to be identified...
February 27, 2018: Structure
Wandayi Emmanuel Amlabu, Ishaya Haruna Nock, Naveen Kumar Kaushik, Dinesh Mohanakrishnan, Jyoti Tiwary, Patrick Ahmadu Audu, Musbahu S Abubakar, Dinkar Sahal
The plant kingdom continues to hold great promise for the eradication of Malaria infection following the challenges of insecticide resistance by the vector mosquito, drug resistance by the parasite, and the development of a vaccine still being a mirage. Acalypha wilkesiana Muller Argoviensis, 1866 (family: Euphorbiaceae) leaves have the ethnopharmacological reputation for use as a remedy against dermal microbial infections in Nigeria. Here, we have studied the antiplasmodial potential of the extract of the leaves of this ornamental plant...
March 17, 2018: Parasitology Research
Khushbu Shah, Sudhir Raghavan, Zhanjun Hou, Larry H Matherly, Aleem Gangjee
All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics...
February 20, 2018: Journal of Molecular Graphics & Modelling
Mohamed A Abdelgawad, Madlen B Labib, Waleed A M Ali, Gehan Kamel, Amany A Azouz, El-Shaymaa El-Nahass
A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72...
March 8, 2018: Bioorganic Chemistry
Shivani Patel, Palmi Modi, Mahesh Chhabria
Caspase-1 is a key endoprotease responsible for the post-translational processing of pro-inflammatory cytokines IL-1β, 18 & 33. Excessive secretion of IL-1β leads to numerous inflammatory and autoimmune diseases. Thus caspase-1 inhibition would be considered as an important therapeutic strategy for development of newer anti-inflammatory agents. Here we have employed an integrated virtual screening by combining pharmacophore mapping and docking to identify small molecules as caspase-1 inhibitors. The ligand based 3D pharmacophore model was generated having the essential structural features of (HBA, HY & RA) using a data set of 27 compounds...
March 8, 2018: Journal of Molecular Graphics & Modelling
Deepak Reddy Gade, Amareswararao Makkapati, Rajesh Babu Yarlagadda, Godefridus J Peters, B S Sastry, V V S Rajendra Prasad
Overexpression of P-glycoprotein (P-gp) leads to the emergence of multidrug resistance (MDR) in cancer treatment. Acridones have the potential to reverse MDR and sensitize cells. In the present study, we aimed to elucidate the chemosensitization potential of acridones by employing various molecular modelling techniques. Pharmacophore modeling was performed for the dataset of chemosensitizing acridones earlier proved for cytotoxic activity against MCF7 breast cancer cell line. Gaussian-based QSAR studies also performed to predict the favored and disfavored region of the acridone molecules...
February 24, 2018: Computational Biology and Chemistry
Lianbin Yao, Sten Ohlson, Brian W Dymock
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Doodipala Samba Reddy
Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus...
2018: Vitamins and Hormones
Assem Barakat, Abdullah M Al-Majid, Bander M Al-Qahtany, M Ali, Mohamed Teleb, Mohamed H Al-Agamy, Sehrish Naz, Zaheer Ul-Haq
BACKGROUND: Design and synthesis of pyrazole-dimedone derivatives were described by one-pot multicomponent reaction as new antimicrobial agents. These new molecular framework were synthesized in high yields with a broad substrate scope under benign conditions mediated by diethylamine (NHEt2 ). The molecular structures of the synthesized compounds were assigned based on different spectroscopic techniques (1 H-NMR,13 C-NMR, IR, MS, and CHN). RESULTS: The synthesized compounds were evaluated for their antibacterial and antifungal activities against S...
March 14, 2018: Chemistry Central Journal
Ronald Domalaon, Temilolu Idowu, George G Zhanel, Frank Schweizer
The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades...
April 2018: Clinical Microbiology Reviews
Han Gao, Gang Li, Hong-Xiang Lou
Exploration of structurally novel natural products greatly facilitates the discovery of biologically active pharmacophores that are biologically validated starting points for the development of new drugs. Endophytes that colonize the internal tissues of plant species, have been proven to produce a large number of structurally diverse secondary metabolites. These molecules exhibit remarkable biological activities, including antimicrobial, anticancer, anti-inflammatory and antiviral properties, to name but a few...
March 13, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yurii L Zborovskii, Viktor V Orysyk, Iuliia Golovynska, Olena I Dzhus, Liudmyla V Garmanchuk, Iurii V Stepanov, Natalia Khranovska, Anatolii O Nehelia, Sergii Golovynskyi, Tymish Y Ohulchanskyy, Junle Qu, Svitlana I Orysyk, Vasyl I Pekhno, Myhaylo V Vovk
BACKGROUND: One of the most promising strategies to develop multi-targeted anticancer therapeutics is to introduce to the structure of a potential drug two or more pharmacophores (functional groups or structural fragments), which have antiproliferative, proapoptotic or antimetastatic properties acting via different mechanisms. OBJECTIVE: To design, synthesize and perform screening of a novel hybrid anticancer compound. METHOD: A novel hybrid compound 4-[(E)-2-phenylethenesulfonamido]-N-hydroxybutanamide, combining butanehydroxamate and styrenesulfonamide moieties, was designed, synthesized and investigated as a potent antimetastatic and antiproliferative agent...
March 13, 2018: Anti-cancer Agents in Medicinal Chemistry
Marcin D Tomala, Katarzyna Magiera-Mularz, Katarzyna Kubica, Sylwia Krzanik, Bartosz Zieba, Bogdan Musielak, Marcin Pustula, Grzegorz M Popowicz, Michael Sattler, Grzegorz Dubin, Lukasz Skalniak, Tad A Holak
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a...
March 5, 2018: European Journal of Medicinal Chemistry
Sonia de Castro, María-José Camarasa
HIV infection still has a serious health and socio-economical impact and is one of the primary causes of morbidity and mortality all over the world. HIV infection and the AIDS pandemic are still matters of great concern, especially in less developed countries where the access to highly active antiretroviral therapy (HAART) is limited. Patient compliance is another serious drawback. Nowadays, HAART is the treatment of choice although it is not the panacea. Despite the fact that it suppresses viral replication at undetectable viral loads and prevents progression of HIV infection into AIDS HAART has several pitfalls, namely, long-term side-effects, drug resistance development, emergence of drug-resistant viruses, low compliance and the intolerance of some patients to these drugs...
March 5, 2018: European Journal of Medicinal Chemistry
Renren Bai, Jian Sun, Zhongxing Liang, Younghyoun Yoon, Eric Salgado, Amber Feng, Yoonhyeun Oum, Yuanyuan Xie, Hyunsuk Shim
The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells...
March 2, 2018: European Journal of Medicinal Chemistry
Xueping Hu, Bin Yin, Kaat Cappelle, Luc Swevers, Guy Smagghe, Xinling Yang, Li Zhang
Insect growth is regulated by the steroid hormone 20-hydroxyecdysone (20E), which works via the ecdysone receptor (EcR). To identify biologically active and novel ecdysone agonists/antagonists, ligand/structure-based virtual screening combined with pharmacophore modeling and molecular docking was performed to identify novel nonsteroidal lead compounds. Nine molecules were screened and selected for an in vitro cell-based reporter bioassay. The results showed that VS-006 and VS-009 exhibited antagonistic activity in S2 cells, whereas only VS-006 exhibited antagonistic activity in Bm5 cells...
March 2, 2018: Journal of Molecular Graphics & Modelling
Ma'mon M Hatmal, Mutasem O Taha
We previously combined molecular dynamics (classical or simulated annealing) with ligand-receptor contacts analysis as means to extract valid pharmacophore model(s) from single ligand-receptor complexes. However, molecular dynamics methods are computa-tionally expensive and time consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within reasonable time scale. The new method is based on ligand-receptor contacts analysis following en-ergy relaxation of predetermined set of randomly deformed complexes generated from the targeted crystallographic structure...
March 12, 2018: Journal of Chemical Information and Modeling
Satya Prakash Shukla, D Gomika Udugamasooriya
We recently identified a peptide-peptoid hybrid, PPS1, which specifically recognized lipid-phosphatidylserine (PS). PPS1 consists of distinct positively charged and hydrophobic residue-containing regions. PPS1 monomer was inactive, but the dimeric form, PPS1D1, displayed strong cytotoxicity for lung cancer cells compared to normal cells in vitro, and reduced the tumor growth in vivo. The minimum pharmacophore of PPS1D1 showed that the first (methionine) and fourth (N-lysine) residues were not important for PPS1D1 cytotoxic activity...
December 1, 2017: MedChemComm
Sujith Rajan, Sabbu Satish, Kripa Shankar, Sukanya Pandeti, Salil Varshney, Ankita Srivastava, Durgesh Kumar, Abhishek Gupta, Sanchita Gupta, Rakhi Choudhary, Vishal M Balaramnavar, Tadigoppula Narender, Anil N Gaikwad
BACKGROUND AND PURPOSE: In our drug discovery program of natural product, earlier we have reported Aegeline that is N-acylated-1-amino-2- alcohol, which was isolated from the leaves of Aeglemarmelos showed anti-hyperlipidemic activity for which the QSAR studies predicted the compound to be the β3-AR agonist, but the mechanism of its action was not elucidated. In our present study, we have evaluated the β3-AR activity of novel N-acyl-1-amino-3-arylopropanol synthetic mimics of aegeline and its beneficial effect in insulin resistance...
March 7, 2018: Metabolism: Clinical and Experimental
Amelie Perron, Yoshihiro Nishikawa, Jun Iwata, Hiromi Shimojo, Junichiro Takaya, Kumiko Kobayashi, Itaru Imayoshi, Naasson Mbambi Mbenza, Mihoko Takenoya, Ryoichiro Kageyama, Yuzo Kodama, Motonari Uesugi
The transcription factor Hes family bHLH transcription factor 1 (Hes1) is a downstream effector of Notch signaling and plays a crucial role in orchestrating developmental processes during the embryonic stage. However, its aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the present study, we report the discovery of small organic molecules (JI051 and JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1) via an interaction domain comprising two tryptophan residues, prompting us to search a chemical library of 1,800 small molecules enriched for indole-like π-electron-rich pharmacophores for a compound that blocks Hes1-mediated transcriptional repression...
March 9, 2018: Journal of Biological Chemistry
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