In Vitro modeling of angiotensin-converting enzyme inhibitor's absorption with chromatographic retention data and selected molecular descriptors

Odović, Jadranka; Marković, Bojan; Vladimirov, Sote; Karljiković‐Rajić, Katarina

doi:10.1016/j.jchromb.2014.02.004

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…The use of ACEis in experimental animal models has revealed that these medicines have a protective effect on tumor development. Captopril, an ACE that is commonly used as an antihypertensive medicine in clinical settings, dramatically decreased tumor growth, angiogenesis, and tumor diameters in xenograft models while boosting mice survival [ 334 , 335 , 336 , 337 ]. Furthermore, the AT1R blocker Candesartan totally decreased expression of the angiogenesis-related gene (VEGF and hypoxia-inducible transcription factor 2 (HIF-2)) and significantly reduced tumor growth, vascularization as well as lung metastases [ 338 , 339 , 340 ].…”

Section: Key Individual Gpcrs and Their Signaling Pathways Involved In Various Cancermentioning

confidence: 99%

An Insight into GPCR and G-Proteins as Cancer Drivers

Chaudhary

Kim

2021

Cells

108

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G-protein-coupled receptors (GPCRs) are the largest family of cell surface signaling receptors known to play a crucial role in various physiological functions, including tumor growth and metastasis. Various molecules such as hormones, lipids, peptides, and neurotransmitters activate GPCRs that enable the coupling of these receptors to highly specialized transducer proteins, called G-proteins, and initiate multiple signaling pathways. Integration of these intricate networks of signaling cascades leads to numerous biochemical responses involved in diverse pathophysiological activities, including cancer development. While several studies indicate the role of GPCRs in controlling various aspects of cancer progression such as tumor growth, invasion, migration, survival, and metastasis through its aberrant overexpression, mutations, or increased release of agonists, the explicit mechanisms of the involvement of GPCRs in cancer progression is still puzzling. This review provides an insight into the various responses mediated by GPCRs in the development of cancers, the molecular mechanisms involved and the novel pharmacological approaches currently preferred for the treatment of cancer. Thus, these findings extend the knowledge of GPCRs in cancer cells and help in the identification of therapeutics for cancer patients.

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Section: Key Individual Gpcrs and Their Signaling Pathways Involved In Various Cancermentioning

confidence: 99%

An Insight into GPCR and G-Proteins as Cancer Drivers

Chaudhary

Kim

2021

Cells

108

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“…Fragment contributions were determined by least squares fitting to the single conformer 3D PSA for 34,810 drugs from the World Drug Index. TPSA data usually provides results of virtually the same quality as classical 3D PSA; calculations, however, were 2–3 orders of magnitude faster 35,36…”

Section: Methodsmentioning

confidence: 99%

“…TPSA data usually provides results of virtually the same quality as classical 3D PSA; calculations, however, were 2–3 orders of magnitude faster. 35 , 36 …”

Section: Methodsmentioning

confidence: 99%

Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands

Sadek¹,

Schreeb²,

Schwed³

et al. 2014

DDDT

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A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2–7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N4-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N4-benzyl-N2-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (ki =4.49±1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5–650 nM), moderate to low hH4R affinity (4,500–30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8–6,500), and promising calculated drug-likeness properties.

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“…A number authors have studied various antihypertensive drugs, including CCBs, their design and synthesis [12,13], pharmacokinetics, pharmacodynamics and efficacy [14][15][16][17]. We have examined the correlations between the calculated molecular descriptors, mainly the lipophilicity of selected antihypertensive drugs, their PPB data, absorption and elimination in established and appropriate models [18][19][20][21][22]. The aim of the present study was to estimate the relationship between plasma protein binding data of nine CCBs (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil and diltiazem) and their in silico molecular properties.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the relationship between the molecular properties of calcium channel blockers and plasma protein binding data

Odović¹,

Trbojević

Trbojević-Stanković

et al. 2017

ARCH BIOL SCI BELGRA

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In this study we investigated the relationship between the calcium channel blockers (CCBs), amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil and diltiazem, and their calculated molecular descriptors: polar surface area (PSA), molecular weight (Mw), volume value (Vol), aqueous solubility data (logS), lipophilicity (logP), acidity (pKa values) and plasma protein binding (PPB) data, obtained from relevant literature. The relationships between the computed molecular properties of selected CCBs and their PPB data were investigated by simple linear regression analysis that revealed very low correlations (R2<0.35). When multiple linear regression (MLR) analysis was applied to investigate reliable correlations between the CCBs' calculated molecular descriptors and PPB data, the best correlations were found for the relationships between CCBs, and PPB data and lipophilicity, and with application of the molecular descriptor (Mw, Vol, or pKa) data as additional independent variables (R2=0.623; R2=0.741; R2=0.657, respectively), with an acceptable probability value (P<0.05), confirming that lipophilicity, together with other molecular properties, are essential for the drugs' PPB. We conclude that this could be considered as an additional in vitro approach for modeling CCBs.

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In Vitro modeling of angiotensin-converting enzyme inhibitor's absorption with chromatographic retention data and selected molecular descriptors

Cited by 14 publications

References 25 publications

An Insight into GPCR and G-Proteins as Cancer Drivers

An Insight into GPCR and G-Proteins as Cancer Drivers

Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands

Assessment of the relationship between the molecular properties of calcium channel blockers and plasma protein binding data

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