Read by QxMD icon Read

Virtual screening

Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
Marilia N N Lima, Cleber C Melo-Filho, Gustavo C Cassiano, Bruno J Neves, Vinicius M Alves, Rodolpho C Braga, Pedro V L Cravo, Eugene N Muratov, Juliana Calit, Daniel Y Bargieri, Fabio T M Costa, Carolina H Andrade
Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium , affecting more than 200 million people worldwide every year and leading to about a half million deaths. Malaria parasites of humans have evolved resistance to all current antimalarial drugs, urging for the discovery of new effective compounds. Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum ( Pf dUTPase) induces wrong insertions in plasmodial DNA and consequently leading the parasite to death, this enzyme is considered an attractive antimalarial drug target...
2018: Frontiers in Pharmacology
Ummi Ammarah, Amit Kumar, Rajesh Pal, Naresh C Bal, Gauri Misra
Microtubule associated serine/threonine kinase (MASTL) is an important Ser/Thr kinase belonging to the family of AGC kinases. It is the human orthologue of Greatwall kinase (Gwl) that plays a significant role in mitotic progression and cell cycle regulation. Upregulation of MASTL in various cancers and its association with poor patient survival establishes it as an important drug target in cancer therapy. Nevertheless, the target remains unexplored with the paucity of studies focused on identification of inhibitors against MASTL, which emphasizes the relevance of our present study...
March 20, 2018: Scientific Reports
Gurkamaljit Kaur, Bharati Pandey, Arbind Kumar, Naina Garewal, Abhinav Grover, Jagdeep Kaur
The lipolytic protein LipU was conserved in mycobacterium sp. including M. tuberculosis (MTB LipU) and M. leprae (MLP LipU). The MTB LipU was identified in extracellular fraction and was reported to be essential for the survival of mycobacterium. Therefore to address the problem of drug resistance in pathogen, LipU was selected as a drug target and the viability of finding out some FDA approved drugs as LipU inhibitors in both the cases was explored. Three dimensional (3D) model structures of MTB LipU and MLP LipU were generated and stabilized through molecular dynamics (MD)...
March 20, 2018: Journal of Biomolecular Structure & Dynamics
Tanuj Sharma, Mohammad Imran Siddiqi
Unique intrinsic properties of peptides like low toxicity, high biological activity and specificity make them attractive therapeutic agents. PDZ binding peptide inhibitors have been demonstrated for curing of Alzheimer, Parkinson, Dementia and other central nervous system ailments. In this article, we report the successful use of an integrated computational protocol to analyze the structural basis of how peptides bind to the shallow groove of the third PDZ domain (PDZ3) from the Post Synaptic Density (PSD-95) protein...
March 20, 2018: Journal of Biomolecular Structure & Dynamics
Irene Maffucci, Xiao Hu, Valentina Fumagalli, Alessandro Contini
Nwat-MMGBSA is a variant of MM-PB/GBSA based on the inclusion of a number of explicit water molecules that are the closest to the ligand in each frame of a molecular dynamics trajectory. This method demonstrated improved correlations between calculated and experimental binding energies in both protein-protein interactions and ligand-receptor complexes, in comparison to the standard MM-GBSA. A protocol optimization, aimed to maximize efficacy and efficiency, is discussed here considering penicillopepsin, HIV1-protease, and BCL-XL as test cases...
2018: Frontiers in Chemistry
Rola M Labib, Radhakrishnan Srivedavyasasri, Fadia S Youssef, Samir A Ross
Pinus roxburghii is highly popular as a potent analgesic and anti-inflammatory agent; however its exact mechanism of action was not fully elucidated. We aimed to interpret the analgesic and anti-inflammatory activity of the total ethanol extract of Pinus roxburghii bark (PRE) and its isolated compounds by both in silico molecular modelling and in-vitro cannabinoid and opioid binding activities evaluation for the first time. Comprehensive phytochemical investigation of PRE resulted in the isolation of sixteen compounds that were fully elucidated using1 H NMR and13 C NMR...
March 2018: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Tanzeel Ur Rehman, Arif-Ullah Khan, Azar Abbas, Javid Hussain, Farman Ullah Khan, Kimberly Stieglitz, Shamsher Ali
In the present study, we describe various pharmacological effects and computational analysis of nepetolide, a tricyclic clerodane-type diterpene, isolated from Nepeta suavis . Nepetolide concentration-dependently (1.0-1000 µg/mL) exhibited 1,1-diphenyl,2-picrylhydrazyl free radical scavenging activity with maximum effect of 87.01 ± 1.85%, indicating its antioxidant potential, as shown by standard drug, ascorbic acid. It was moderately active against bacterial strain of Staphylococcus aureus . In brine shrimp's lethality model, nepetolide potently showed cytotoxic effect, with LC50 value of 8...
March 2018: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Daniel Mattle, Bernd Kuhn, Johannes Aebi, Marc Bedoucha, Demet Kekilli, Nathalie Grozinger, Andre Alker, Markus G Rudolph, Georg Schmid, Gebhard F X Schertler, Michael Hennig, Jörg Standfuss, Roger J P Dawson
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Nivedita Rai, R Muthukumaran, R Amutha
The HtrA protease of Helicobacter pylori, which efficiently colonizes at the gastric epithelial of host cells, disrupts the mucosal integrity of E-cadherin and spreads inflammatory diseases including gastric cancer by cleaving the cell-cell adhesion of the host. The lack of knowledge on the molecular diversity, structural and functional behavior of HpHtrA necessitated the present study to explore its inhibition mechanism. At first, the similarity of HpHtrA with other gastro-intestinal pathogenic HtrA bacteria and its remote relationship with the Human HtrA homologs were ensured by the phylogenetic analysis and hence was identified as a novel therapeutic target for further design of inhibitors...
March 16, 2018: Microbial Pathogenesis
Barend L Penzhorn, Edward C Netherlands, Courtney A Cook, Nico J Smit, Ilse Vorster, Robert F Harrison-White, Marinda C Oosthuizen
BACKGROUND: Domestic dogs are not native to sub-Saharan Africa, which may account for their susceptibility to Babesia rossi, of which endemic black-backed jackals (Canis mesomelas) are natural reservoirs. There is virtually no information on the occurrence of potentially pathogenic haemogregarines (e.g. Hepatozoon canis) or even rickettsial bacteria (e.g. Ehrlichia spp. and Anaplasma spp.) in indigenous canids in sub-Saharan Africa. Such organisms could pose a risk to domestic dogs, as well as to populations of endangered indigenous canid species...
March 20, 2018: Parasites & Vectors
Yawen Dong, Xi Jiang, Tian Liu, Yun Ling, Qing Yang, Li Zhang, Xiongkui He
Chitinases play a vital part in the molting phase of insect pests. Inhibiting their activities by the use of drug-like small chemical molecules is thought to be an efficient strategy in pesticide design and development. Based on the crystal structure of OfChtI, a chitinase indispensable for molting of the insect pest Ostrinia furnacalis (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of OfChtI obtained from a library of over 200,000 chemicals by a structure-based virtual screening approach...
March 20, 2018: Journal of Agricultural and Food Chemistry
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
Valeria La Pietra, Stefania Sartini, Lorenzo Botta, Alessandro Antonelli, Silvia Martina Ferrari, Poupak Fallahi, Alessio Moriconi, Vito Coviello, Luca Quattrini, Yi-Yu Ke, Hsieh Hsing-Pang, Federico Da Settimo, Ettore Novellino, Concettina La Motta, Luciana Marinelli
It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET...
March 2, 2018: European Journal of Medicinal 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
Julia B Jasper, Lina Humbeck, Tobias Brinkjost, Oliver Koch
Protein ligand interaction fingerprints are a powerful approach for the analysis and assessment of docking poses to improve docking performance in virtual screening. In this study, a novel interaction fingerprint approach (PADIF, protein per atom score contributions derived interaction fingerprint) is presented which was specifically designed for utilising the GOLD scoring functions' atom contributions together with a specific scoring scheme. This allows the incorporation of known protein-ligand complex structures for a target-specific scoring...
March 16, 2018: Journal of Cheminformatics
Anne Deblock-Bellamy, Charles Sebiyo Batcho, Catherine Mercier, Andreanne K Blanchette
BACKGROUND: Proprioceptive sense plays a significant role in the generation and correction of skilled movements and, consequently, in most activities of daily living. We developed a new proprioception assessment protocol that enables the quantification of elbow position sense without using the opposite arm, involving active movement of the evaluated limb or relying on working memory. The aims of this descriptive study were to validate this assessment protocol by quantifying the elbow position sense of healthy adults, before using it in individuals who sustained a stroke, and to investigate its test-retest reliability...
March 16, 2018: Journal of Neuroengineering and Rehabilitation
Ya Chen, Yong Tang, Beibei Mao, Wenchao Li, Hongwei Jin, Liangren Zhang, Zhenming Liu
Any type of breast cancer not expressing genes of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) is referred to as triple-negative breast cancer (TNBC). Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-yl)benzenesulfonamides as selective inhibitors of TNBCs...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Lucia Romero, Jordi Cano, Julio Gomis-Tena, Beatriz Trenor, Ferran Sanz, Manuel Pastor, Javier Saiz
Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue...
March 16, 2018: Journal of Chemical Information and Modeling
Jamal Shamsara
Rescoring is a simple approach that theoretically could improve the original docking results. In this study AutoDock Vina was used as a docked engine and three other scoring functions besides the original scoring function, Vina, as well as their combinations as consensus scoring functions were employed to explore the effect of rescoring on virtual screenings that had been done on diverse targets. Rescoring by DrugScore produces the most number of cases with significant changes in screening power. Thus, the DrugScore results were used to build a simple model based on two binding site descriptors that could predict possible improvement by DrugScore rescoring...
2018: International Journal of Medicinal Chemistry
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"