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https://www.readbyqxmd.com/read/28549890/-18-f-labeled-indole-based-analogs-as-highly-selective-radioligands-for-imaging-sigma-2-receptors-in-the-brain
#1
Liang Wang, Jiajun Ye, Yingfang He, Winnie Deuther-Conrad, Jinming Zhang, Xiaojun Zhang, Mengchao Cui, Jörg Steinbach, Yiyun Huang, Peter Brust, Hongmei Jia
We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity (Ki=1.79-5.23nM) for σ2 receptors and high subtype selectivity (Ki (σ2)/Ki (σ1)=56-708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [(18)F]16 and [(18)F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10-15% radiochemical yield and radiochemical purity of >99%...
May 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28544162/benzimidazole-scaffold-as-anticancer-agent-synthetic-approaches-and-structure-activity-relationship
#2
REVIEW
Neelima Shrivastava, Mohd Javed Naim, Md Jahangir Alam, Farah Nawaz, Shujauddin Ahmed, Ozair Alam
Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body. Benzimidazole is an organic compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 8...
May 22, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28540949/structure-based-in-silico-identification-of-potentially-non-steroidal-brassinosteroids-mimics
#3
Beilei Lei, Ningjuan Heng, Xiaoxue Dang, Jiyuan Liu, Xiaojun Yao, Cunli Zhang
Brassinosteroids (BRs) are a class of plant steroid hormones that play indispensable roles in cell elongation, division and plant development. To date, the numerous synthesis of BRs analogs and structure-activity relationship investigations have clearly revealed the key substituent groups relevant to the steroidal activity of BRs. However, due to the limited chemical space studied, the efforts for alternative non-steroidal compounds have produced no remarkable results. To identify potentially non-steroidal BR mimics in this study, vital interacting pharmacophore features were extracted starting from several complex structures of BRs that bound with the receptor Brassinosteroid-Insentive 1 (BRI1) and co-receptor BRI1-associated kinase 1 (BAK1), which were characterized and merged into one comprehensive pharmacophore model...
May 25, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28535470/pharmacophore-guided-discovery-of-small-molecule-interleukin-15-inhibitors
#4
Barbara Żyżyńska-Granica, Bartosz Trzaskowski, Szymon Niewieczerzał, Sławomir Filipek, Oliwia Zegrocka-Stendel, Małgorzata Dutkiewicz, Piotr Krzeczyński, Magdalena Kowalewska, Katarzyna Koziak
Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28535034/p450-mediated-non-natural-cyclopropanation-of-dehydro-alanine-containing-thiopeptides
#5
Joshua G Gober, Swapnil V Ghodge, Jonathan W Bogart, Walter J Wever, Richard R Watkins, Eric M Brustad, Albert A Bowers
Thiopeptides are a growing class of ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. Many biosynthetic enzymes for RiPPs, especially thiopeptides, are promiscuous and can accept a wide range of peptide substrates with different amino acid sequence; thus, these enzymes have been used as tools to generate new natural product derivatives. Here, we explore an alternative route to molecular complexity by engineering thiopeptide tailoring enzymes to do new or non-native chemistry...
May 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28534839/exploring-the-pivotal-role-of-the-ck2-hinge-region-sub-pocket-in-binding-with-tricyclic-quinolone-analogues-by-computational-analysis
#6
Yue Zhou, Na Zhang, Shan Tang, Xiaoqian Qi, Lijiao Zhao, Rugang Zhong, Yongzhen Peng
Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM) and 27h (IC50 > 1000 nM) to CK2 is abolished. However, the unbinding mechanisms due to the key pharmacophore group replacement of compounds 27e and 27h are unveiled. In the present work, combined computational analysis was performed to investigate the underlying structural basis of the low-affinity of two systems...
May 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28533114/2-aminomethylthieno-3-2-d-pyrimidin-4-3h-ones-bearing-3-methylpyrazole-hinge-binding-moiety-highly-potent-selective-and-time-dependent-inhibitors-of-cdc7-kinase
#7
Osamu Kurasawa, Misaki Homma, Yuya Oguro, Tohru Miyazaki, Kouji Mori, Noriko Uchiyama, Kenichi Iwai, Akihiro Ohashi, Hideto Hara, Sei Yoshida, Nobuo Cho
In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity...
May 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28531818/pharmacophore-searching-a-potential-solution-for-correcting-unknown-ligands-unk-labelling-errors-in-protein-data-bank-pdb-s
#8
Musadiq Ibrahim, Adrian Jonathan Lapthorn, Mohammad Ibrahim
The Protein Data Bank (PDB) is the single most important repository of structural data for proteins and other biologically relevant molecules. Therefore, it is critically important to keep the PDB data, error-free as much as possible. In this study, we have critically examined PDB structures of 292 protein molecules which have been deposited in the repository along with potentially incorrect ligands labelled as Unknown ligands (UNK). Pharmacophores were generated for all the protein structures by using Discovery Studio Visualizer (DSV) and Accelrys, Catalyst(®)...
April 4, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28531373/identification-of-potential-inhibitors-for-hcv-ns3-genotype-4a-by-combining-protein-ligand-interaction-fingerprint-3d-pharmacophore-docking-and-dynamic-simulation
#9
Mahmoud Abd El-Monem El-Hasab, Eman Esmat El-Bastawissy, Tarek Faathy El-Moselhy
HCV NS3 protease domain has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting HCV genotype 1 infection. HCV genotype 4a dominant in Egypt has paid less attention. Here we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS3 of genotype 4a using homology modelling, PLIF (protein ligand interaction fingerprint), docking, pharmacophore and dynamic simulation...
May 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28530540/novel-n-mustard-benzimidazoles-benzothiazoles-hybrids-synthesis-and-anticancer-evaluation
#10
Dilip P Detroja, Tai-Lin Chen, Yi-Wen Lin, Tsai-Yi Yen, Ming-Hsi Wu, Tung-Hu Tsai, Krunal Maheriya, Rajesh Kakadiya, Te-Chang Lee, Anamik Shah, Tsann-Long Su
BACKGROUND: Bendamustine, an N-mustard-benzoimidazole hybrid conjugate, was recently approved for the treatment of chronic lymphocytic leukemia. However, the short half-life of bendamustine may limit its clinical applications. OBJECTIVE: The purpose of this study is to design and synthesize compounds with a more favorable pharmacokinetic profile. METHODS: We synthesized a series of hybrid molecules comprising a phenyl N-mustard moiety and benzothiazole or benzimidazole scaffold linked via an ureido linker and evaluated their antitumor activity and plasma stability...
May 22, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28529634/novel-linear-peptides-with-high-affinity-to-%C3%AE-v%C3%AE-3-integrin-for-precise-tumor-identification
#11
Yi Ma, Guanhua Ai, Congying Zhang, Menglu Zhao, Xue Dong, Zhihao Han, Zhaohui Wang, Min Zhang, Yuxi Liu, Weidong Gao, Siwen Li, Yueqing Gu
Development of alternative linear peptides for targeting αvβ3 integrin has attracted much attention, as the traditional peptide ligand, cyclic RGD, is limited by inferior water-solubility and complex synthesis. Using pharmacophore-based virtual screening and high-throughput molecular docking, we identified two novel linear small peptides RWr and RWrNM with high affinity and specificity to αvβ3 integrin. The competitive binding with cyclic RGD (c(RGDyK)) and cellular uptake related to the integrin expression levels verified their affinity to αvβ3 integrin...
2017: Theranostics
https://www.readbyqxmd.com/read/28528302/nanomolar-anti-sickling-compounds-identified-by-ligand-based-pharmacophore-approach
#12
Odailson Santos Paz, Milena de Jesus Pinheiro, Renan Fernandes do Espirito Santo, Cristiane Flora Villarreal, Marcelo Santos Castilho
Adenosine receptors are considered as potential targets for drug development against several diseases. The discovery of subtype 2B adenosine receptors role in erythrocyte sickling process proved its importance to neglected diseases such as sickle cell anemia, which affects approximately 29.000 people around the world, but whose treatment is restricted to just one FDA approved drug (hydroxyurea). In order to widen the therapeutic arsenal available to treat sickle cell anemia patients, it is imperative to identify new lead compounds that modify the sickling course and not just its symptoms...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28523727/synthesis-and-antineoplastic-evaluation-of-mitochondrial-complex-ii-succinate-dehydrogenase-inhibitors-derived-from-atpenin-a5
#13
Hezhen Wang, Bader Huwaimel, Kshitij Verma, James Miller, Todd Germain, Nihar Kinarivala, Dimitri Pappas, Paul Brookes, Paul Charles Trippier
Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogues of the CII inhibitor natural product atpenin A5 were prepared to evaluate the structure-activity relationship of the C-5 pyridine side chain. The side chain ketone moiety was determined to be pharmacophoric, engendering a bioactive conformation. Analogue 16c displayed CII IC50 = 64 nM, retained selectivity for CII over mitochondrial complex I (>156-fold) and possessed a ligand-lipophilicity efficiency of 5...
May 18, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28523625/identification-of-a-novel-putative-inhibitor-of-the-plasmodium-falciparum-purine-nucleoside-phosphorylase-exploring-the-purine-salvage-pathway-to-design-new-antimalarial-drugs
#14
Luciano Porto Kagami, Gustavo Machado das Neves, Ricardo Pereira Rodrigues, Vinicius Barreto da Silva, Vera Lucia Eifler-Lima, Daniel Fábio Kawano
Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria...
May 18, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/28521820/destabilization-of-the-twist1-e12-complex-dimerization-following-the-r154p-point-mutation-of-twist1-an-in-silico-approach
#15
Charlotte Bouard, Raphael Terreux, Agnès Tissier, Laurent Jacqueroud, Arnaud Vigneron, Stéphane Ansieau, Alain Puisieux, Léa Payen
BACKGROUND: The bHLH transcription factor TWIST1 plays a key role in the embryonic development and in tumorigenesis. Some loss-of-function mutations of the TWIST1 gene have been shown to cause an autosomal dominant craniosynostosis, known as the Saethre-Chotzen syndrome (SCS). Although the functional impacts of many TWIST1 mutations have been experimentally reported, little is known on the molecular mechanisms underlying their loss-of-function. In a previous study, we highlighted the predictive value of in silico molecular dynamics (MD) simulations in deciphering the molecular function of TWIST1 residues...
May 18, 2017: BMC Structural Biology
https://www.readbyqxmd.com/read/28518069/modification-and-functionalization-of-the-guanidine-group-by-tailor-made-precursors
#16
Tobias G Kapp, Maximilian Fottner, Horst Kessler
The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes αv and α5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document...
April 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28514875/identification-of-novel-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-using-computational-approaches
#17
Manish Kesherwani, Sriram Raghavan, Krishnasamy Gunasekaran, Devadasan Velmurugan
Nicotinamide Phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of NAD. Cancer cells have elevated poly [ADP-Ribose] polymerase 1 (PARP) activity as well as the immense necessity of ATP: thereby consuming NAD at a higher rate than normal tissues. The perturbation of these intracellular processes is more sensitive and highly dependent on NAMPT to maintain the required NAD levels. Functional inhibition of NAMPT is, therefore, a promising drug target in therapeutic oncology. In this study, the importance of intermolecular contacts was realized based on contact occupancy and favorable energetic from molecular dynamic simulation to discern non-critical contacts of four different classes of potential NAMPT inhibitor bound complexes...
May 17, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28511907/potential-inhibitors-of-human-carbonic-anhydrase-isozymes-i-and-ii-design-synthesis-and-docking-studies-of-new-1-3-4-thiadiazole-derivatives
#18
Mehlika Dilek Altıntop, Belgin Sever, Ahmet Özdemir, Kaan Kucukoglu, Hicran Onem, Hayrunnisa Nadaroglu, Zafer Asım Kaplancıklı
In the last years, inhibition of carbonic anhydrase (CA) has emerged as a promising approach for pharmacologic intervention in a variety of disorders such as glaucoma, epilepsy, obesity, and cancer. As a consequence, the design of CA inhibitors (CAIs) is a highly dynamic field of medicinal chemistry. Due to the therapeutic potential of thiadiazoles as CAIs, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their inhibitory effects on hCA I and hCA II. Although the tested compounds did not carry a sulfonamide group, an important pharmacophore for CA inhibitory activity, it was a remarkable finding that most of them were more effective on hCAs than acetazolamide (AAZ), the reference agent...
May 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28506753/phenylbenzenesulfonates-and-sulfonamides-as-17%C3%AE-hydroxysteroid-dehydrogenase-type-2-inhibitors-synthesis-and-sar-analysis
#19
Anna Vuorinen, Roger T Engeli, Susanne Leugger, Christoph R Kreutz, Daniela Schuster, Alex Odermatt, Barbara Matuszczak
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the potent estrogen estradiol into the weakly active keto form estrone. Because of its expression in bone, inhibition of 17β-HSD2 provides an attractive strategy for the treatment of osteoporosis, a condition that is often caused by a decrease of the active sex steroids. Currently, there are no drugs on the market targeting 17β-HSD2, but in multiple studies, synthesis and biological evaluation of promising 17β-HSD2 inhibitors have been reported...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28503546/computational-tool-for-fast-in-silico-evaluation-of-herg-k-channel-affinity
#20
Giulia Chemi, Sandra Gemma, Giuseppe Campiani, Simone Brogi, Stefania Butini, Margherita Brindisi
The development of a novel comprehensive approach for the prediction of hERG activity is herein presented. Software Phase has been used to derive a 3D-QSAR model, employing as alignment rule a common pharmacophore built on a subset of 22 highly active compounds (threshold Ki: 50 nM) against hERG K(+) channel. Five features comprised the pharmacophore: two aromatic rings (R1 and R2), one hydrogen-bond acceptor (A), one hydrophobic site (H), and one positive ionizable function (P). The sequential 3D-QSAR model developed with a set of 421 compounds (randomly divided in training and test set) yielded a test set (Q(2)) = 0...
2017: Frontiers in Chemistry
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