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https://www.readbyqxmd.com/read/28094550/pharmacophore-modelling-atom-based-3d-qsar-generation-and-virtual-screening-of-molecules-projected-for-mpges-1-inhibitory-activity
#1
S Misra, M Saini, H Ojha, D Sharma, K Sharma
COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors...
January 17, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28092830/trpv1-antagonism-by-piperazinyl-aryl-compounds-a-topomer-comfa-study-and-its-use-in-virtual-screening-for-identification-of-novel-antagonists
#2
Rajendra Kristam, Shashidhar N Rao, Anne Sudha D'Cruz, Vijayalakshmi Mahadevan, Vellarkad N Viswanadhan
Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field...
January 7, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28092392/the-in-silico-identification-of-human-bile-salt-export-pump-abcb11-inhibitors-associated-with-cholestatic-drug-induced-liver-injury
#3
Lili Xi, Jia Yao, Yuhui Wei, Xin'an Wu, Xiaojun Yao, Huanxiang Liu, Shuyan Li
Drug-induced liver injury (DILI) is one of the major causes of drug attrition and failure. Currently, there is increasing evidence that direct inhibition of the human bile salt export pump (BSEP/ABCB11) by drugs and/or metabolites is one of the most important mechanisms of cholestatic DILI. In the present study, we employ two in silico methods, random forest (RF) and the pharmacophore method, to recognize potential BSEP inhibitors that could cause cholestatic DILI, with the aim of mitigating the risk of cholestatic DILI to some extent...
January 16, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28088519/phytochemicals-as-multi-target-inhibitors-of-the-inflammatory-pathway-a-modeling-and-experimental-study
#4
Nisha S Devi, Meera Ramanan, Padmapriya Paragi-Vedanthi, Mukesh Doble
The arachidonic acid pathway consists of several enzymes and targeting them is favored for developing anti-inflammatory drugs. However, till date the current drugs are generally active against a single target, leading to undesirable side-effects. Phytochemicals are known to inhibit multiple targets simultaneously and hence, an attempt is made here to investigate their suitability. A pharmacophore based study is performed with three sets of reported phytochemicals namely, dual 5-LOX/mPGES1, alkaloids and FLAP inhibitors...
January 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28088445/synthesis-and-exploration-of-novel-radiolabeled-bombesin-peptides-for-targeting-receptor-positive-tumor
#5
Kakali De, Indranil Banerjee, Samarendu Sinha, Shantanu Ganguly
Increasing evidence of peptide receptor overexpression in various cancer cells, warrant the development of receptor specific radiolabeled peptides for molecular imaging and therapy in nuclear medicine. Gastrin-releasing-peptide (GRP) receptor, are overexpressed in a variety of human cancer cells. The present study report the synthesis and biological evaluation of new bombesin (BBN) analogs, HYNIC-Asp-[Phe(13)]BBN(7-13)-NH-CH2-CH2-CH3:BA1, HYNIC-Pro-[Tyr(13)Met(14)]BBN(7-14)NH2:BA2 as prospective tumor imaging agent with compare to BBN(7-14)NH2:BS as standard...
January 11, 2017: Peptides
https://www.readbyqxmd.com/read/28079013/natural-product-inhibitors-of-topoisomerases-review-and-docking-study
#6
L Scotti, F J B Mendonça Júnior, F F Ribeiro, J F Tavares, M S Da Silva, J M Barbosa Filho, M T Scotti
Since ancient times, natural products have been used in treating various diseases effectively and safely. Nowadays, these natural compounds are submitted to sophisticated methodologies from isolation, computing, analytical, and even serving as pharmacophore suggestions for synthesis. The substances extracted from marine species, plants, and microorganisms present activities beneficial to our health, including protection against malignant tumors. The topoisomerase enzymes play an important role in DNA metabolism, and searching for enzyme inhibitors is an important target in the search for new anticancer drugs...
January 11, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28078985/designing-isoform-selective-inhibitors-against-classical-hdacs-for-effective-anticancer-therapy-insight-and-perspectives-from-in-silico
#7
Shabir Ahmad Ganai
Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting...
12, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28075359/development-of-pharmacophore-model-for-indeno-1-2-b-indoles-as-human-protein-kinase-ck2-inhibitors-and-database-mining
#8
Samer Haidar, Zouhair Bouaziz, Christelle Marminon, Tuomo Laitinen, Antti Poso, Marc Le Borgne, Joachim Jose
Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors...
January 9, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28072524/common-hits-approach-combining-pharmacophore-modeling-and-molecular-dynamics-simulations
#9
Marcus Wieder, Arthur Garon, Ugo Perricone, Stefan Boresch, Thomas Seidel, Anna Maria Almerico, Thierry Langer
We present a new approach that incorporates flexibility based on extensive MD simulations of protein-ligand complexes into structure based pharmacophore modeling and virtual screening. The approach uses the multiple coordinate sets saved during the MD simulations and generates for each frame a pharmacophore model. Pharmacophore models with the same pharmacophore features are pooled. In this way the high number of pharmacophore models that results from the MD simulation is reduced to only a few hundred representative pharmacophore models...
January 10, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28071341/identification-of-novel-hits-as-highly-prospective-dual-agonists-for-mu-and-kappa-opioid-receptors-an-integrated-in-silico-approach
#10
Indrani Bera, Mrinal Vishwas Marathe, Pavan V Payghan, Nanda Ghoshal
Opioid agonists are used clinically for the treatment of acute and chronic pain, however, their clinical use is limited due to the presence of undesired side effects. Dual agonists, simultaneously targeting mu and kappa opioid receptors, show fewer side effects than that of selective agonists. In the present work, 2D- and 3D- Quantitative Structure Activity Relationship studies were performed on a series of aminomorphinan derivatives as dual agonists, using a wide range of descriptors. The aim of the study was to identify the structural requirements for the activity of these compounds towards mu and kappa opioid receptors and using the models, with best external predictability, for predicting the activities of new hits obtained from shape based virtual screening of drug like compounds from ZINC database...
January 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28067432/synthesis-and-neurotrophic-activity-studies-of-illicium-sesquiterpene-natural-product-analogs
#11
Johannes Richers, Alexander Pöthig, Eberhardt Herdtweck, Claudia Sippel, Felix Hausch, Konrad Tiefenbacher
Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only few studies have been conducted in order to investigate a common pharmacophoric motif and the structure-activity relationship. Here, an investigation of structurally more simple analogs of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables the preparation of the carbon framework of () Merrilactone A and () Anislactone A/B in gram-scale...
January 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28067167/6-benzothiazolyl-ureas-thioureas-and-guanidines-are-potent-inhibitors-of-abad-17%C3%AE-hsd10-and-potential-drugs-for-alzheimer-s-disease-treatment-design-synthesis-and-in-vitro-evaluation
#12
Ondrej Benek, Lukas Hroch, Laura Aitken, Rafael Dolezal, Patrick Guest, Marketa Benkova, Ondrej Soukup, Karel Musil, Kamil Kuca, Terry K Smith, Frank Gunn-Moore, Kamil Musilek
BACKGROUND: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/ 17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβ toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. METHODS: As ABAD's enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment...
January 9, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28064083/identification-of-novel-pad4-inhibitors-based-on-a-pharmacophore-model-derived-from-transition-state-coordinates
#13
Yu Wei, Ruihua Liu, Cui Liu, Jin Jin, Dongmei Li, Jianping Lin
1.4 Protein arginine deiminases 4 (PAD4) is an attractive target for the development of novel and selective inhibitors of Rheumatoid Arthritis (RA). F-amidine is known as mechanism-based inhibitor targeting PAD4 and used as inactivators by covalently modifying the active site Cys645. To identify novel structural inhibitors of PAD4, we investigated the flexibility of protein on basis of the transition state geometry of PAD4 inhibited by F-amidine from our previous QM/MM calculation. And a pharmacophore model was generated containing four features (ADHH) using five representative structures from molecular dynamic (MD) simulation on basis of the transition state geometry of PAD4 inhibited by F-amidine...
December 19, 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28063348/the-in-silico-identification-of-small-molecules-for-protein-protein-interaction-inhibition-in-akap-lbc-rhoa-signaling-complex
#14
Asifullah Khan, Mehwish Munir, Sara Aiman, Abdul Wadood, Arif-Ullah Khan
The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc-RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade...
December 31, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28061415/an-enantiomer-based-virtual-screening-approach-discovery-of-chiral-organophosphates-as-acetyl-cholinesterase-inhibitors
#15
Aiqian Zhang, Yunsong Mu, Fengchang Wu
Chiral organophosphates (OPs) have been used widely around the world, very little is known about binding mechanisms with biological macromolecules. An in-depth understanding of the stereo selectivity of human AChE and discovering bioactive enantiomers of OPs can decrease health risks of these chiral chemicals. In the present study, a flexible molecular docking approach was conducted to investigate different binding modes of twelve phosphorus enantiomers. A pharmacophore model was then developed on basis of the bioactive conformations of these compounds...
January 3, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28059045/computational-screening-of-ccr5-inhibitors-as-potential-entry-inhibitor-microbicides-using-3d-qsar-studies-docking-and-molecular-dynamics-simulation
#16
Radhika Ramachandran, Muthusankar Aathi, D Durairaj Ruban, Shanmughavel Piramanyagam
BACKGROUND: The chemokine receptor CCR5 acts as a co-receptor for HIV binding and it is considered as an important target by CCR5 antagonists. Entry inhibitor based microbicides gain much importance nowadays as these drugs act at an early stage of HIV lifecycle and thus hinder the viral replication process in humans. The present study intends to identify a CCR5 antagonist which could be developed as a microbicide using computational approaches. METHOD: The pharmacophore modeling and 3D QSAR studies was used to identify CCR5 antagonists with enhanced antagonist activity...
January 6, 2017: Current HIV Research
https://www.readbyqxmd.com/read/28057571/acyl-chain-preference-and-inhibitor-identification-of-moraxella-catarrhalis-lpxa-insight-through-crystal-structure-and-computational-studies
#17
Shivendra Pratap, Pooja Kesari, Ravi Yadav, Aditya Dev, Manju Narwal, Pravindra Kumar
Lipopolysaccharide (LPS) is an important surface component and a potential virulence factor in the pathogenesis of Gram-negative bacteria. UDP-N-acetylglucosamine acyltransferase (LpxA) enzyme catalyzes the first reaction of LPS biosynthesis, reversible transfer of R-3-hydroxy-acyl moiety from donor R-3-hydroxy-acyl-acyl carrier protein to the 3' hydroxyl position of UDP-N-acetyl-glucosamine. LpxA enzyme's essentiality in bacterial survival and absence of any homologous protein in humans makes it a promising target for anti-bacterial drug development...
January 3, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28056740/novel-colchicine-derivatives-and-their-anti-cancer-activity
#18
Lorelei Johnson, Ing Swie Goping, Aja Rieger, Jonathan Y Mane, Torin Huzil, Asok Banerjee, Richard Luduena, Bashar Hassani, Philip Winter, Jack A Tuszynski
In this paper we provide an overview of the status of various colchicine derivatives in pre-clinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin β isotypes, especially in regard to βIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes over-expressed in cancer and decreasing it for normal cells thereby widening the therapeutic window...
January 4, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28056738/microtubule-targeting-agents-as-cancer-chemotherapeutics-an-overview-of-molecular-hybrids-as-stabilising-and-destabilising-agents
#19
Anjana Devi Tangutur, Dinesh Kumar, Kommalapati Vamsi Krishna, Srinivas Kantevari, Anjana Devi Tangutur, Dinesh Kumar, Kommalapati Vamsi Krishna, Srinivas Kantevari
Microtubules form crucial dynamic structural cellular components of the cell and are composed of the alpha beta tubulin heterodimers. Microtubules are involved in a wide variety of functions in the cell such as attribution to cell shape, motility, intracellular trafficking and mitotic spindle formation. Owing to these reasons, tubulin and microtubules have gained significant interest as important targets for cancer therapy. A review of the existing microtubule targeting drugs specifies that these agents can be categorised into two of the major categories: Microtubule stabilising agents such as paclitaxel, docetaxel, epothilones, and discodermolide which bind to the tubulin polymer and stabilize the microtubules, microtubule destabilising agents such as vinca alkaloids, colchicine and combretastatins which bind to tubulin dimers and cause destabilisation...
January 4, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28056499/recognition-of-hiv-inactivating-peptide-triazoles-by-the-recombinant-soluble-env-trimer-bg505-sosip-664
#20
Kriti Acharya, Adel A Rashad, Francesca Moraca, Per Johan Klasse, John P Moore, Cameron Abrams, Irwin Chaiken
Peptide triazole (PT) antagonists interact with gp120 subunits of HIV-1 Env trimers to block host cell receptor interactions, trigger gp120 shedding, irreversibly inactivate virus and inhibit infection. Despite these enticing functions, understanding the structural mechanism of PT-Env trimer encounter has been limited. In this work, we combined competition interaction analysis and computational simulation to demonstrate PT binding to the recombinant soluble trimer, BG505 SOSIP.664, a stable variant that resembles native virus spikes in binding to CD4 receptor as well as known conformationally-dependent Env antibodies...
January 5, 2017: Proteins
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