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Computational drug design

Tiantian Wang, Shiyang Dong, Xiaodong Chen, Kun Qian, Huayu Wang, Hexiu Quan, Zhongli Zhang, Yueming Zuo, Liping Huang, Dongxun Li, Ming Yang, Shilin Yang, Yi Jin, Zengtao Wang
A series of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene)pyrrolidin-2-one derivatives were designed, synthesized, and evaluated for their anticonvulsant activities. In the preliminary screening, compounds 5, 6a-6f and 6h-6i showed promising anticonvulsant activities in MES model, while 6f and 6g represented protection against seizures at doses of 100 mg/kg and 0.5 h in scPTZ model. The most active compound 6d had a high-degree protection against the MES-induced seizures with ED50 value of 4.3 mg/kg and TD50 value of 160...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Sanghamitra Mohanty, Prasant Mohanty, Chintan Trivedi, Carola Gianni, Domenico G Della Rocca, Luigi Di Biase, Andrea Natale
BACKGROUND: This meta-analysis systematically evaluated the outcome of pulmonary vein isolation (PVI) with and without focal impulse and rotor modulation (FIRM) ablation in patients with atrial fibrillation. METHODS AND RESULTS: Extensive literature search was performed for studies reporting outcomes of PVI alone and PVI+FIRM procedures. For PVI alone, only randomized trials conducted in the past 3 years reporting single-procedure off-antiarrhythmic drugs success rate at ≥12-month follow-up were included...
March 2018: Circulation. Arrhythmia and Electrophysiology
Akhil Kumar, Ashish Tiwari, Ashok Sharma
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target...
March 15, 2018: Current Neuropharmacology
Sheikh Arslan Sehgal, Mirza A Hammad, Rana Adnan Tahir, Hafiza Nisha Akram, Faheem Ahmad
BACKGROUND: As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. OBJECTIVE: To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases...
March 15, 2018: Current Neuropharmacology
Amit Kumar, Francesca Pintus, Amalia Di Petrillo, Rosaria Medda, Paola Caria, Maria João Matos, Dolores Viña, Enrico Pieroni, Francesco Delogu, Benedetta Era, Giovanna L Delogu, Antonella Fais
Alzheimer's disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated...
March 13, 2018: Scientific Reports
Hermann Blessberger, Juergen Kammler, Hans Domanovits, Oliver Schlager, Brigitte Wildner, Danyel Azar, Martin Schillinger, Franz Wiesbauer, Clemens Steinwender
BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia...
March 13, 2018: Cochrane Database of Systematic Reviews
Daniel J Mermelstein, Charles Lin, Gard Nelson, Rachael Kretsch, J Andrew McCammon, Ross C Walker
Alchemical free energy (AFE) calculations based on molecular dynamics (MD) simulations are key tools in both improving our understanding of a wide variety of biological processes and accelerating the design and optimization of therapeutics for numerous diseases. Computing power and theory have, however, long been insufficient to enable AFE calculations to be routinely applied in early stage drug discovery. One of the major difficulties in performing AFE calculations is the length of time required for calculations to converge to an ensemble average...
March 12, 2018: Journal of Computational Chemistry
Laurent Batiste, Andrea Unzue, Aymeric Dolbois, Fabrice Hassler, Xuan Wang, Nicholas Deerain, Jian Zhu, Dimitrios Spiliotopoulos, Cristina Nevado, Amedeo Caflisch
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment...
February 28, 2018: ACS Central Science
Patricia Santofimia-Castaño, Bruno Rizzuti, Olga Abián, Adrián Velázquez-Campoy, Juan L Iovanna, José L Neira
BACKGROUND: NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions...
March 9, 2018: Biochimica et Biophysica Acta
Abid Qureshi, Akanksha Rajput, Gazaldeep Kaur, Manoj Kumar
A number of anti-retroviral drugs are being used for treating Human Immunodeficiency Virus (HIV) infection. Due to emergence of drug resistant strains, there is a constant quest to discover more effective anti-HIV compounds. In this endeavor, computational tools have proven useful in accelerating drug discovery. Although methods were published to design a class of compounds against a specific HIV protein, but an integrated web server for the same is lacking. Therefore, we have developed support vector machine based regression models using experimentally validated data from ChEMBL repository...
March 9, 2018: Journal of Cheminformatics
Rohit Shukla, Harish Shukla, Timir Tripathi
Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a crucial enzyme of the glyoxylate cycle and is a validated anti-tuberculosis drug target. Structurally distant, non-active site mutation (H46A) in MtbICL has been found to cause loss of enzyme activity. The aim of the present work was to explore the structural alterations induced by H46A mutation that caused the loss of enzyme activity. The structural and dynamic consequences of H46A mutation were studied using multiple computational methods such as docking, molecular dynamics simulation and residue interaction network analysis (RIN)...
January 2018: Tuberculosis
Hugo Aguilar-Díaz, Karen E Nava-Castro, Galileo Escobedo, Lenin Domínguez-Ramírez, Martín García-Varela, Víctor H Del Río-Araiza, Margarita I Palacios-Arreola, Jorge Morales-Montor
BACKGROUND: We have previously reported that progesterone (P4 ) has a direct in vitro effect on the scolex evagination and growth of Taenia solium cysticerci. Here, we explored the hypothesis that the P4 direct effect on T. solium might be mediated by a novel steroid-binding parasite protein. METHODS: By way of using immunofluorescent confocal microscopy, flow cytometry analysis, double-dimension electrophoresis analysis, and sequencing the corresponding protein spot, we detected a novel PGRMC in T...
March 9, 2018: Parasites & Vectors
Vladimir Potemkin, Maria Grishina
Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described...
March 8, 2018: Current Medicinal Chemistry
Xuemei Zhao, Chengcai Xia, Xiaodan Wang, Hao Wang, Ming Xin, Long Yu, Yulong Liang
Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis - trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC...
2018: Frontiers in Pharmacology
Sofía S Villar
In a rare life-threatening disease setting the number of patients in the trial is a high proportion of all patients with the condition (if not all of them). Further, this number is usually not enough to guarantee the required statistical power to detect a treatment effect of a meaningful size. In such a context, the idea of prioritizing patient benefit over hypothesis testing as the goal of the trial can lead to a trial design that produces useful information to guide treatment, even if it does not do so with the standard levels of statistical confidence...
April 2018: Probability in the Engineering and Informational Sciences
Yan Li, Minyi Su, Zhihai Liu, Jie Li, Jie Liu, Li Han, Renxiao Wang
Scoring functions are a group of computational methods widely applied in structure-based drug design for fast evaluation of protein-ligand interactions. To date, a whole spectrum of scoring functions have been developed based on different assumptions or algorithms. Therefore, it is important to both the end users and the developers of scoring functions that their performance be objectively assessed. We have developed the comparative assessment of scoring functions (CASF) benchmark as an open-access solution for scoring function evaluation...
April 2018: Nature Protocols
Rona R Ramsay, Alen Albreht
Monoamine oxidases (MAOs) catalyse the oxidation of neurotransmitter amines and a wide variety of primary, secondary and tertiary amine xenobiotics, including therapeutic drugs. While inhibition of MAO activity in the periphery removes protection from biogenic amines and so is undesirable, inhibition in the brain gives vital antidepressant and behavioural advantages that make MAO a major pharmaceutical target for inhibitor design. In neurodegenerative diseases, MAO inhibitors can help to maintain neurotransmitter levels, making it a common feature in novel multi-target combinations designed to combat Alzheimer's disease, albeit not yet proven clinically...
March 7, 2018: Journal of Neural Transmission
Hongbin Yang, Lixia Sun, Weihua Li, Guixia Liu, Yun Tang
During drug development, safety is always the most important issue, including a variety of toxicities and adverse drug effects, which should be evaluated in preclinical and clinical trial phases. This review article at first simply introduced the computational methods used in prediction of chemical toxicity for drug design, including machine learning methods and structural alerts. Machine learning methods have been widely applied in qualitative classification and quantitative regression studies, while structural alerts can be regarded as a complementary tool for lead optimization...
2018: Frontiers in Chemistry
Srinivasareddy Putluri, Md Zia Ur Rahman, Shaik Yasmeen Fathima
Cloud computing offers significant research and economic benefits to healthcare organisations. Cloud services provide a safe place for storing and managing large amounts of such sensitive data. Under conventional flow of gene information, gene sequence laboratories send out raw and inferred information via Internet to several sequence libraries. DNA sequencing storage costs will be minimised by use of cloud service. In this study, the authors put forward a novel genomic informatics system using Amazon Cloud Services, where genomic sequence information is stored and accessed for processing...
February 2018: Healthcare Technology Letters
Qianqian Zhao, Nikhila Miriyala, Yan Su, Weijie Chen, Xuejiao Gao, Ling Shao, Yitao Wang, Ru Yan, Haifeng Li, Xiao-Jun Yao, Dong-Sheng Cao, Defang Ouyang
Cyclodextrin (CD) complexation is widely used for the solubilization of poorly soluble drugs in the pharmaceutical industry. Current research was to develop a highly-soluble lutein-cyclodextrin multiple-component delivery system (lutein-CD-MCDS) by combined modeling and experimental approaches. Both phase solubility diagram and molecular dynamics (MD) simulation results revealed that the interactions between lutein and CDs were very weak, which confirmed the insignificant solubility improvement of lutein-CD binary system...
March 5, 2018: Molecular Pharmaceutics
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