Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

Srivani, P.; Sastry, G. Narahari

doi:10.1016/j.jmgm.2008.10.010

Cited by 34 publications

(17 citation statements)

References 41 publications

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“…The second conserved cluster of amino acids in C/EK is found specifically in members of the C/EK family and is referred to as the CK motif. Previous site-directed mutagenesis studies and structural studies in Caenorhabditis elegans CKA-2 and the analysis of the crystal structures of human CKa2 highlighted the importance of several of the amino acids involved in the binding of ATP and the stabilization of the transition state of the reaction and served as the basis for the structure-based design of inhibitors (38)(39)(40). Usually, CK can use both choline and ethanolamine as substrates, even though choline is the preferred one, whereas EKs are generally specific for ethanolamine.…”

Section: The Choline and Ethanolamine Kinasesmentioning

confidence: 99%

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

2010

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SummaryThe glycerophospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) account for greater than 50% of the total phospholipid species in eukaryotic membranes and thus play major roles in the structure and function of those membranes. In most eukaryotic cells, PC and PE are synthesized by an aminoalcoholphosphotransferase reaction, which uses sn-1,2-diradylglycerol and either CDP-choline or CDP-ethanolamine, respectively. This is the last step in a biosynthetic pathway known as the Kennedy pathway, so named after Eugene Kennedy who elucidated it over 50 years ago. This review will cover various aspects of the Kennedy pathway including: each of the biosynthetic steps, the functions and roles of the phospholipid products PC and PE, and how the Kennedy pathway has the potential of being a chemotherapeutic target against cancer and various infectious diseases. IUBMBIUBMB Life, 62(6): [414][415][416][417][418][419][420][421][422][423][424][425][426][427][428] 2010

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Section: The Choline and Ethanolamine Kinasesmentioning

confidence: 99%

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

2010

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“…UNITY molecular fingerprints (UFPs) with a bit length of 992 were generated using the default settings in UNITY (Tripos). QSAR holograms with bin lengths of 97, 151, 199, 257, 307, 353, 3,500, and 10,000 and fragment lengths of 4 to 7 atoms, with nonhydrogen fragment atoms, bonds, and connections used to determine uniqueness, were generated using the HQSAR module of SYBYL (24,38). Each HQSAR analysis of biological data for CQ-susceptible and CQ-resistant parasites produced the same estimate for the optimum hologram bin length (10,000), which was used for all subsequent analyses.…”

Section: Qsar Analyses (I) Molecular Alignmentmentioning

confidence: 99%

“…Partial atomic charges were calculated using the Gasteiger-Hückel method (16)(17)(18). The 3-D coordinates of each AQ analogue were imported into the SYBYL molecular modeling suite (24,38) to create molecular databases containing the 108 AQ analogues. All molecules were modeled in the neutral form, since protonation of this highly congeneric series conferred no advantages.…”

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confidence: 99%

4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses

Hocart

Liu

Deng

et al. 2011

Antimicrob Agents Chemother

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Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC 50 s], <25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of <3 or >10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets.The annual burden of malaria is overwhelming, with more than 300 to 500 million cases and 2 million deaths each year (3). In addition, its impact is exacerbated by the increasing prevalence of antimalarial resistance, which was the single most important factor in its recent worldwide resurgence (22,41). The most important resistance is that of Plasmodium falciparum to 7-chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline (chloroquine [CQ]), because P. falciparum is responsible for most morbidity and mortality, and especially for the deaths of children under the age of 5 years in sub-Saharan Africa (3). For these reasons, and because resistance to the artemisinins and to the combination of atovaquone and proguanil (Malarone) is now emerging (14,20,33), the development of antimalarials that are effective against drug-resistant parasites-and that are affordable for the people in the greatest need-is an urgent global health priority.The established safety record of CQ, its ease of synthesis, and its low cost led us to examine the structure-activity relationships (SARs) responsible for the antiparasite activity of the 4-aminoquinolines (AQs) (10,11,26) with the goal of identifying the factors responsible for their activity against CQ-resistant parasites. The design and synthesis of AQ analogues during the past 5 to 10 years, in combination with biological te...

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“…Compound minimization was done using OPLS 2005 Force field. The protein and compound preparation by docking was done as per the earlier procedure (Srivani and Sastry, 2009). …”

Section: Protein and Ligand Preparationmentioning

confidence: 99%

A facile and single pot strategy for the synthesis of novel naphthyridine derivatives under microwave irradiation conditions using ZnCl2 as catalyst, evaluation of AChE inhibitory activity, and molecular modeling studies

et al. 2011

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A series of novel naphthyridine derivatives 3 and 4 was prepared from substituted pyridine 2 and ketones using ZnCl 2 as catalyst under microwave irradiation conditions. All the compounds were evaluated for AChE inhibitory activity and promising compounds 3d, 3e, 4b, and 4g was identified. Representative compounds 3d and 3e were found to show insignificant THLE-2 liver cell viability/toxicity. The binding mode between X-ray crystal structure of human AChE and compounds was studied using molecular docking method and fitness scores were found to be in good correlation with the activity data.

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Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

Cited by 34 publications

References 41 publications

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses

A facile and single pot strategy for the synthesis of novel naphthyridine derivatives under microwave irradiation conditions using ZnCl2 as catalyst, evaluation of AChE inhibitory activity, and molecular modeling studies

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