Modeling calcium channel antagonistic activity of dihydropyridine derivatives using QTMS indices analyzed by GA-PLS and PC-GA-PLS

Mohajeri, Afshan; Hemmateenejad, Bahram; Mehdipour, Ahmad Reza; Miri, Ramin

doi:10.1016/j.jmgm.2007.09.002

Cited by 50 publications

(33 citation statements)

References 38 publications

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“…Furthermore, the results of compounds show that addition of phenyl group in position 4 in this type of dihydropyridines significantly reduces the activity in asymmetrical compounds since compounds 16 and 17 are more than 50 times weaker than their corresponding derivatives (18 and 19) which lack the phenyl group. This finding is consistent with previous investigation demonstrating the significant role of C4 aryl in the calcium channel antagonist activity of DHPs (Edraki et al, 2009;Mohajeri et al, 2008). In fact, it is supposed that the conformation of C4 aryl is very deterministic in differentiating between agonist and antagonist activity of DHP.…”

Section: Pharmacologysupporting

confidence: 93%

“…Also, it was shown that C4 aryl is probably one of three parts of DHP in interaction with target (Ca channel) (Mohajeri et al, 2008). In this case, as presence of additional phenyl group resulted in considerable reduction in calcium channel antagonist activity, it can be hypothesized that such an addition may produce a steric hindrance which makes the interaction with channel more difficult.…”

Section: Pharmacologymentioning

confidence: 96%

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Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possessing 4-pyrone moieties

et al. 2010

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New 1,4-dihydropyridine derivatives were synthesized by introducing 4-pyrone ring systems at the 4-position of the dihydropyridine nucleus. These compounds were obtained according to Hantzsch reaction. 4-Pyrone carbaldehydes: 4-(4-oxo-6-phenyl-4H-pyran-2-yl)-benzaldehyde 4a, 4-(6-methyl-4-oxo-4H-pyran-2-yl)benzaldehyde 4b, 4-oxo-6-phenyl-4H-pyran-2-carbaldehyde 7a, and 6-methyl-4-oxo-4H-pyran-2-carbaldehyde 7b were synthesized and used in these reactions. Then, the calcium channel blocking activity of some of these compounds were evaluated in which they showed weak effects.

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Section: Pharmacologysupporting

confidence: 93%

Section: Pharmacologymentioning

confidence: 96%

Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possessing 4-pyrone moieties

et al. 2010

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“…Those collinear descriptors (r>0.9) were removed and 367 descriptors were still retained, which was still a problem to select the most relevant descriptors. Two variable selection approaches, simulated annealing-based partial least 28) and genetic algorithms based partial least squares (GA-PLS) 28,29) came to the rescue. PLS2 served to correlate both sets of anti-inflammatory activity data simultaneously with the structural descriptors, which is an extension to PLS1, allowing the modeling and/or prediction of multiple responses.…”

Section: Resultsmentioning

confidence: 99%

Relationship of Chemical Structure to <i>in Vitro</i> Anti-inflammatory Activity of Tirucallane Triterpenoids from the Stem Barks of <i>Aphanamixis grandifolia</i>

Guo

Wang

Zhang

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of tirucallane triterpenoids isolated from the stem barks of Aphanamixis grandifolia were assessed for their anti-inflammatory activity, exhibiting from weak to strong anti-inflammatory activity, by testing their inhibitory effects on nitric oxide (NO) production and tumor necrosis factor-α (TNF-α) level in lipopolysaccharide (LPS) induced RAW264.7 murine macrophages. To explore the relationship between the structures and anti-inflammatory activity, a vast pool of molecular descriptors for each isolate were calculated. Genetic algorithms (GA) or simulated annealing (SA) based partial least squares (GA-PLS and SA-PLS) algorithms identified some important descriptor combinations, which were correlated with both sets of the anti-inflammatory data by partial least squares 2 (PLS2) method. S-Plot was used to visualize the descriptor influence in the PLS2 model, disclosed five most important molecular descriptors, nOHt, RDF150m, lip_vio-lation, Mor32m and JhetZ.Key words Aphanamixis grandifolia; tirucallane triterpenoid; anti-inflammatory activity; nitric oxide; tumor necrosis factor-α; structure-activity relationship Inflammation is a normal and crucial response of the organism to various stimuli including physical damage, ultra violet irradiation, microbial invasion and immune reactions, playing a pivotal role in host defense.1,2) While inflammatory cascades may cause pain, tissue damage, and a wide range of human acute and chronic inflammatory diseases, such as chronic asthma, rheumatoid arthritis and multiple sclerosis, and psoriasis.3) Many of these diseases with increasing incidence rate are particularly debilitating to the patient's functional capacity and quality of life.Macrophages have vital functions in maintaining body homeostasis, as well as in inflammatory processes, which are endowed with the ability to release a variety of mediators including the free radical nitric oxide (NO), 4) one of the most versatile regulator in the immune system. 5) Overproduction of NO can exacerbate inflammation, playing an important role in the pathogenesis of several chronic and systemic inflammation diseases, such as rheumatoid arthritis. 6,7)Tumor necrosis factor-α (TNF-α), one of the most important pro-inflammatory cytokines, is also massively produced by the activated macrophages and monocytes at local sites of inflammation.8) Its excessive production further triggers the secretion of other inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and thereby aggravates the inflammation in many autoimmune/inflammatory diseases. 9-11)Exposure to major anti-inflammatory agents, such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), is known to increase substantially the risk of serious side effects.3,12) Therefore, there is an unmet medical need for new treatment strategies, which could be possibly filled by rational phytopharmaceuticals with a favorable benefit/risk ratio. Recent investigations into the anti-inflamm...

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“…The GA used here was demonstrated in other literature (Mohajeri et al, 2008) Therefore, only the important points about this study are described here. Where the number of independent variables is more than molecules, subset selection is necessary for avoiding chance correlation.…”

Section: Training and Test Setsmentioning

confidence: 99%

Comparative quantitative structure–activity relationship study of some 1-aminocyclopentyl-3-carboxyamides as CCR2 inhibitors using stepwise MLR, FA-MLR, and GA-PLS

et al. 2010

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Multiple linear regression (MLR), factor analysis in combination with multiple linear regression (FA-MLR), and genetic algorithm subset selection partial least square (GA-PLS) regression methods were used for quantitative structure-activity relationships (QSAR) model building. These approaches were employed to investigate the correlation between pIC 50 and various physicochemical descriptors of 28 compounds of 1-aminocyclopentyl-3-carboxyamides including substituted tetrahydropyran moieties as CCR2 inhibitors. The obtained models were validated using cross-validation and external test set. The predictability and robustness of the developed models were considered by some figures of merit such as RMSEP and Y-randomization. MLR, FA-MLR, and GA-PLS have R 2 equal to 0.84, 0.69, and 0.93, respectively. Predicted variance by MLR, FA-MLR, and GA-PLS (R 2 test) is 78, 75, and 78%, respectively. Furthermore, the domain of applicability which indicates the area of reliable predictions is defined. The prediction results by models are in good agreement with the experimental value.

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Modeling calcium channel antagonistic activity of dihydropyridine derivatives using QTMS indices analyzed by GA-PLS and PC-GA-PLS

Cited by 50 publications

References 38 publications

Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possessing 4-pyrone moieties

Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possessing 4-pyrone moieties

Relationship of Chemical Structure to <i>in Vitro</i> Anti-inflammatory Activity of Tirucallane Triterpenoids from the Stem Barks of <i>Aphanamixis grandifolia</i>

Comparative quantitative structure–activity relationship study of some 1-aminocyclopentyl-3-carboxyamides as CCR2 inhibitors using stepwise MLR, FA-MLR, and GA-PLS

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