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drug discovery

Bamigboye J Taiwo, Olujide O Olubiyi, Fanie R van Heerden
Nigerian medicinal plants have been demonstrated to be veritable source of lead compounds for drug discovery efforts. One such example is mangiferin. Mangiferin was originally isolated from the Nigerian plant Ceiba pentandra (Mombacaceae), after which its structure was elucidated with the aid of spectroscopy. Mangiferin, a xanthone glycoside, has also been reported in certain other plant families including Gentianaceae and Anacardiaceae. In certain other climes and different parts of the world, folkloric and traditional medicine has extensively employed Mangifera indica (another source of mangiferin) in treating different diseases...
March 20, 2018: Current Computer-aided Drug Design
Xun Liu, Yang Zhang, Zhanhong Hu, Qian Li, Lu Yang, Guoqiang Xu
The ubiquitin proteasome system (UPS) plays important roles in the regulation of protein stability, localization, and activity. A myriad of studies have focused on the functions of ubiquitin ligases E3s and deubiquitinating enzymes DUBs due to their specificity in the recognition of downstream substrates. However, the roles of the most ubiquitin-conjugating enzymes E2s are not completely understood except that they transport the activated ubiquitin and form E2-E3 protein complexes. Ubiquitin-conjugating enzyme CDC34 can promote the degradation of downstream targets through the UPS whereas its non-catalytic functions are still elusive...
March 21, 2018: Protein Journal
Yaxia Yuan, Fang Zheng, Chang-Guo Zhan
Blood-brain barrier (BBB) permeability of a compound determines whether the compound can effectively enter the brain. It is an essential property which must be accounted for in drug discovery with a target in the brain. Several computational methods have been used to predict the BBB permeability. In particular, support vector machine (SVM), which is a kernel-based machine learning method, has been used popularly in this field. For SVM training and prediction, the compounds are characterized by molecular descriptors...
March 21, 2018: AAPS Journal
Adnane Aouidate, Adib Ghaleb, Mounir Ghamali, Samir Chtita, Abdellah Ousaa, M'barek Choukrad, Abdelouahid Sbai, Mohammed Bouachrine, Tahar Lakhlifi
BACKGROUND: Quantitative structure-activity relationship (QSAR) was carried out to study a series of aminooxadiazoles as PIM1 inhibitors having pki ranging from 5.59 to 9.62 (ki in nM). The present study was performed using Genetic Algorithm method of variable selection (GFA), multiple linear regression analysis (MLR) and non-linear multiple regression analysis (MNLR) to build unambiguous QSAR models of 34 substituted aminooxadiazoles toward PIM1 inhibitory activity based on topological descriptors...
March 22, 2018: Chemistry Central Journal
Eric H Jung, David J Meyers, Jürgen Bosch, Arturo Casadevall
Similarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity...
March 2018: MSphere
Ensaf M Al-Hujaily, Tanvir Khatlani, Zeyad Alehaideb, Rizwan Ali, Bader Almuzaini, Bahauddeen M Alrfaei, Jahangir Iqbal, Imadul Islam, Shuja Malik, Bader A Marwani, Salam Massadeh, Atef Nehdi, Barrak Alsomaie, Bader Debasi, Ibraheem Bushnak, Saeed Noibi, Syed Hussain, Wahid Abdul Wajid, Jean-Pierre Armand, Sheraz Gul, Julen Oyarzabal, Rana Rais, Chas Bountra, Ahmed Alaskar, Bander Al Knawy, Mohamed Boudjelal
The 'Therapeutics discovery: From bench to first in-human trials' conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10-12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China...
March 2018: Biomedical Reports
Weihsu C Chen, Christopher M Murawsky
Therapeutic molecules derived from antibodies have become a dominant class of drugs used to treat human disease. Increasingly, therapeutic antibodies are discovered using transgenic animal systems that have been engineered to express human antibodies. While the engineering details differ, these platforms share the ability to raise an immune response that is comprised of antibodies with fully human idiotypes. Although the predominant transgenic host species has been mouse, the genomes of rats, rabbits, chickens, and cows have also been modified to express human antibodies...
2018: Frontiers in Immunology
Florencia Díaz-Viraqué, María Laura Chiribao, Andrea Trochine, Fabiola González-Herrera, Christian Castillo, Ana Liempi, Ulrike Kemmerling, Juan Diego Maya, Carlos Robello
The discovery that trypanosomatids, unicellular organisms of the order Kinetoplastida, are capable of synthesizing prostaglandins raised questions about the role of these molecules during parasitic infections. Multiple studies indicate that prostaglandins could be related to the infection processes and pathogenesis in trypanosomatids. This work aimed to unveil the role of the prostaglandin F2 α synthase Tc OYE in the establishment of Trypanosoma cruzi infection, the causative agent of Chagas disease. This chronic disease affects several million people in Latin America causing high morbidity and mortality...
2018: Frontiers in Immunology
Paul C Jordan, Sarah K Stevens, Jerome Deval
Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population...
January 2018: Antiviral Chemistry & Chemotherapy
Cameron A Wade, Natasha Kyprianou
The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis...
March 19, 2018: International Journal of Molecular Sciences
Isaac Fernández-Gómez, Marquiza Sablón-Carrazana, Alberto Bencomo-Martínez, Guadalupe Domínguez, Reyna Lara-Martínez, Nelly F Altamirano-Bustamante, Luis Felipe Jiménez-García, Karina Pasten-Hidalgo, Rosa Angélica Castillo-Rodríguez, Perla Altamirano, Suchitil Rivera Marrero, Cristina Revilla-Monsalve, Peter Valdés-Sosa, Fabio Salamanca-Gómez, Eulalia Garrido-Magaña, Chryslaine Rodríguez-Tanty, Myriam M Altamirano-Bustamante
Human islet amyloid peptide (hIAPP1-37 ) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1-37 ) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs...
March 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
V Priya, B N Srikumar, B S Shankaranarayana Rao
Performing multiple tasks either simultaneously, in rapid alternation or in succession, is routine in daily life. Further, testing rodents in a battery of tests is common both in drug discovery and behavioral phenotyping research. However, learning of new tasks can be influenced by prior experience(s). There has been some research on 'switching cost' involved in the transition from one behavior to another. However, there has been no specific assessment of the effect of learning an operant paradigm on performance in a spatial memory task and vice versa...
March 12, 2018: Journal of Integrative Neuroscience
Cheng-Xin Gong, Fei Liu, Khalid Iqbal
The amyloid cascade hypothesis has been dominating drug discovery for Alzheimer's disease (AD) for the last two decades. The failure of the development of effective drugs for slowing down or reversing the progression of AD warrants the AD field to consider out-of-the-box thinking and therapeutic approaches. We propose the multifactorial hypothesis of AD, emphasizing that AD is caused by multiple etiological factors, which may result in common brain pathology and functional consequences through several separate but integrated molecular pathways...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Jeffrey Cummings, Aaron Ritter, Kate Zhong
Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Kena Song, Zirui Wang, Ruchuan Liu, Guo Chen, Liyu Liu
Exploring the complicated development of tumors and metastases needs a deep understanding of the physical and biological interactions between cancer cells and their surrounding microenvironments. One of the major challenges is the ability to mimic the complex 3-D tissue microenvironment that particularly influences cell proliferation, migration, invasion, and apoptosis in relation to the extracellular matrix (ECM). Traditional cell culture is unable to create 3-D cell scaffolds resembling tissue complexity and functions, and, in the past, many efforts were made to realize the goal of obtaining cell clusters in hydrogels...
March 21, 2018: International Journal of Molecular Sciences
Ritika S Joshi, Dipanwita Das Mukherjee, Subhendu Chakrabarty, Ansie Martin, Manojkumar Jadhao, Gopal Chakrabarti, Angshuman Sarkar, Sujit Kumar Ghosh
In the development of small molecule drug candidates, naphthalimide based compounds hold a very important position as potent anti-cancer agents with considerable safety in drug discoveries. Being synthetically and readily accessible, naphthalimide compounds with planar architecture have been developed mostly as DNA targeting intercalators. However, in this article, we demonstrate, for the first time, wherein an unfused naphthalimide-benzothiazole bichromophoric compound 2-(6-chlorobenzo[d] thiazol-2-yl)-1H-benzo[de] isoquinoline-1,3(2H)-dione (CBIQD), designed and synthesized by our group, seem to expand the bioactivity of naphthalimide as anti-mitotic agents also...
March 21, 2018: Journal of Physical Chemistry. B
Robert M Stoekenbroek, John J P Kastelein
PURPOSE OF REVIEW: This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid-lowering agents. RECENT FINDINGS: PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target...
March 20, 2018: Current Opinion in Cardiology
Mariel M Cardenas, Sean T Toenjes, Christopher J Nalbandian, Jeffrey L Gustafson
The catalytic enantioselective synthesis of 3-aryl-substituted pyrrolopyrimidines (PPYs), a common motif in drug discovery, is achieved through a kinetic resolution via quaternary ammonium salt-catalyzed nucleophilic aromatic substitution (SN Ar). Both enantioenriched products and starting materials can be functionalized with no observed racemization to give enantiodivergent access to diverse chiral analogues of an important class of kinase inhibitor. One of the compounds was found to be a potent and selective inhibitor of breast tumor kinase...
March 21, 2018: Organic Letters
Minji Jeon, Sunkyu Kim, Sungjoon Park, Heewon Lee, Jaewoo Kang
BACKGROUND: Drug combination therapy, which is considered as an alternative to single drug therapy, can potentially reduce resistance and toxicity, and have synergistic efficacy. As drug combination therapies are widely used in the clinic for hypertension, asthma, and AIDS, they have also been proposed for the treatment of cancer. However, it is difficult to select and experimentally evaluate effective combinations because not only is the number of cancer drug combinations extremely large but also the effectiveness of drug combinations varies depending on the genetic variation of cancer patients...
March 19, 2018: BMC Systems Biology
Sailendra Singh, Pallavi Pandey, Sumit Ghosh, Suchitra Banerjee
Andrographolide (AD) is the time-honoured pharmacologically active constituent of the traditionally renowned medicinal plant-Andrographis paniculata. Advancements in the target-oriented drug discovery process have further unravelled the immense therapeutic credibility of another unique molecule-neoandrographolide (NAD). The escalated market demand of these anti-cancer diterpenes is increasingly facing unrelenting hurdles of demand and supply disparity, attributable to their limited yield. Callus and adventitious root cultures were generated to explore their biosynthetic potentials which first time revealed NAD production along with AD...
March 20, 2018: Protoplasma
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