Application of electron conformational–genetic algorithm approach to 1,4-dihydropyridines as calcium channel antagonists: pharmacophore identification and bioactivity prediction

Geçen, Nazmiye; Sarıpınar, Emin; Yanmaz, Ersin; Şahin, Kader

doi:10.1007/s00894-011-1024-5

Cited by 23 publications

(8 citation statements)

References 58 publications

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“…This nontraditional activation of Akt by HCMV allows the increased expression of a select subset of Akt-dependent antiapoptotic proteins specifically required for the survival of infected monocytes past the critical 48-h cell fate checkpoint (20,22,33). activity (39,42,62). The SHIP1 product, PI(3,4)P 2 , binds with greater affinity to Akt, resulting in a greater phosphorylation of Akt compared to the level of phosphorylation achieved with PI(3,4,5)P 3 (42).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes

Cojohari

Peppenelli

Chan

2016

J Virol

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Human cytomegalovirus (HCMV) is a pervasive herpesvirus responsible for significant morbidity and mortality among immunodeficient/naive hosts. Following a primary HCMV infection, circulating blood monocytes mediate the systemic spread of the virus. Extending the short 48-h life span of monocytes is critical to the viral dissemination process, as these blood-borne cells are nonpermissive for virus replication until they are fully differentiated into macrophages. Here, we show that HCMV glycoprotein gB binding to cellular epidermal growth factor receptor (EGFR) during HCMV entry initiated a rapid (within 15 min) activation of the apoptosis suppressor Akt, which was maintained through 72 h. The virus-induced activation of Akt was more robust than that with the normal myeloid growth factor macrophage colony-stimulating factor (M-CSF) and was essential for infected monocytes to bypass the 48-h viability checkpoint. Activation of phosphoinositide 3-kinase (PI3K) following EGFR engagement by HCMV mediated the phosphorylation of Akt. Moreover, HCMV entry drove a switch away from the PI3K p110␦ isoform, which was required for the viability of uninfected monocytes, to the p110␤ isoform in order to facilitate the Akt-dependent prosurvival state within infected cells. Simultaneously, in contrast to M-CSF, HCMV promoted a rapid increase in SH2 domaincontaining inositol 5-phosphatase 1 (SHIP1) expression, leading to signaling through a noncanonical Akt activation pathway. To ensure maximum Akt activity, HCMV also induced an early phosphorylation-dependent inactivation of the negative regulator phosphatase and tensin homolog. Overall, our data indicate that HCMV hijacks the upstream Akt signaling network to induce a nontraditional activation of Akt and subsequently a prosurvival decision at the 48-h cell fate checkpoint, a vital step for HCMV's dissemination and persistence strategy. IMPORTANCEHCMV is found throughout the world with a prevalence of 55 to 100% within the human population. HCMV infection is generally asymptomatic in immunocompetent or naive individuals but is a significant cause of morbidity and mortality among the immunocompromised. Widespread organ inflammation is associated with symptomatic infections, which is a direct consequence of the viral dissemination strategy. Inflammatory peripheral blood monocytes facilitate the spread of HCMV. However, HCMV must subvert the naturally short life span of monocytes. In this work, we demonstrate that HCMV induces the activation of Akt, an antiapoptotic protein, in a manner distinct from that of normal myeloid growth factors. Moreover, we decipher how HCMV dysregulates the upstream Akt signaling network during viral entry to promote an Akt-dependent prosurvival state following infection. Delineation of the virus-specific mechanisms that regulate cellular prosurvival pathways in order to drive the survival of HCMV-infected monocytes is important to identifying new anti-HCMV therapeutic targets. Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus, with th...

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes

Cojohari

Peppenelli

Chan

2016

J Virol

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“…Data for experimental values of pIC 50 are taken from ref. 12. General chemical structures of used molecules and nifedipine are represented in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…All QSAR models are built with application of statistical (mathematical) tools correlating properties of molecules with descriptors that represent molecular structure 5. The DHP family, in which nifedipine is the prototype, have been the aim of many QSAR studies 6–12.…”

Section: Introductionmentioning

confidence: 99%

SMILES‐Based QSAR Models for the Calcium Channel‐Antagonistic Effect of 1,4‐Dihydropyridines

Veselinović

Milosavljević

Toropov

et al. 2012

Archiv der Pharmazie

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The activity of 72 1,4-dihydropyridines as calcium channel antagonists was examined. The simplified molecular input-line entry system (SMILES) was used as representation of the molecular structure of the calcium channel antagonists. Quantitative structure-activity relationships (QSARs) were developed using CORAL software (http://www.insilico.eu/CORAL) for four random splits of the data into the training and test sets. Using the Monte Carlo method, the CORAL software generated the optimal descriptors for one-variable models. The reproducibility of each model was tested performing three runs of the Monte Carlo optimization. The obtained results reveal good predictive potential of the applied approach: The correlation coefficients (r(2) ) for the test sets of the four random splits are 0.9571, 0.9644, 0.9836, and 0.9444.

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“…This technique has been effectively implemented as a 4D‐QSAR technique to define the pharmacophore group for benzotriazine, penicilin, triaminotriazine derivatives, pyrazole pyridine, ruthenium(II) arene complexes, and quantitative activity estimates in our past research …”

Section: Introductionmentioning

confidence: 99%

“…This technique has been effectively implemented as a 4D-QSAR technique to define the pharmacophore group for benzotriazine, penicilin, triaminotriazine derivatives, pyrazole pyridine, ruthenium(II) arene complexes, and quantitative activity estimates in our past research. [70][71][72][73][74][75] 2 | MATERIALS AND METHODS In our work, structure-anticancer activity relations have been studied for the group of tetrahydrodibenzazocines by using EC-GA method.…”

Section: Introductionmentioning

confidence: 99%

A novel hybrid method named electron conformational genetic algorithm as a 4D QSAR investigation to calculate the biological activity of the tetrahydrodibenzazosines

Şahin

Sarıpınar

2020

J Comput Chem

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To understand the structure–activity correlation of a group of tetrahydrodibenzazocines as inhibitors of 17β‐hydroxysteroid dehydrogenase type 3, we have performed a combined genetic algorithm (GA) and four‐dimensional quantitative structure–activity relationship (4D‐QSAR) modeling study. The computed electronic and geometry structure descriptors were regulated as a matrix and named as electron‐conformational matrix of contiguity (ECMC). A chemical property‐based pharmacophore model was developed for series of tetrahydrodibenzazocines by EMRE software package. GA was employed to choose an optimal combination of parameters. A model has been developed for estimating anticancer activity quantitatively. All QSAR models were established with 40 compounds (training set), then they were considered for selective capability with additional nine compounds (test set). A statistically valid 4D‐QSAR (Rtraining2=0.856,Rtest2=0.851 and q2 = 0.650) with good external set prediction was obtained.

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Application of electron conformational–genetic algorithm approach to 1,4-dihydropyridines as calcium channel antagonists: pharmacophore identification and bioactivity prediction

Cited by 23 publications

References 58 publications

Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes

Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes

SMILES‐Based QSAR Models for the Calcium Channel‐Antagonistic Effect of 1,4‐Dihydropyridines

A novel hybrid method named electron conformational genetic algorithm as a 4D QSAR investigation to calculate the biological activity of the tetrahydrodibenzazosines

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