Losartan’s molecular basis of interaction with membranes and AT1 receptor

Zoumpoulakis, Panagiotis; Daliani, I.; Zervou, Maria; Kyrikou, Ioanna; Siapi, Eleni; Lambrinidis, George; Mikros, Emmanuel; Mavromoustakos, Thomas

doi:10.1016/s0009-3084(03)00053-7

Cited by 51 publications

(49 citation statements)

References 29 publications

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“…Resveratrol caused more effective lowering of the main phase transition than its trimethylated analog, while the latter at higher molar fractions caused more significant broadening. Pretransition suppression is frequently observed when a drug molecule is incorporated in lipid bilayers (Kyrikou et al 2004a, b;Mavromoustakos et al 1997;Zoumpoulakis et al 2003). This is attributed to perturbation of the headgroup.…”

Section: Resultsmentioning

confidence: 99%

“…It has been previously reported that the proper conformation, orientation, and location of a drug molecule in the membrane are critical for it to reach its site of action and interact productively with that site (Fotakis et al 2010;Kyrikou et al 2004a, b;Martel et al 1993;Mavromoustakos et al 1994;1995a, b, 1997Zoumpoulakis et al 2003). To investigate the orientation of the studied molecules in the DPPC bilayers, MD simulations have been applied.…”

Section: Resultsmentioning

confidence: 99%

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Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

et al. 2011

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In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the headgroup, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC).Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the headgroup. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phasetransition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

et al. 2011

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“…This characteristic has been proved crucial for lateral diffusion through lipid bilayers. 19,20) Interestingly, 5a has significantly lower lipophilic area (ca. 20 Å 2 ) compared to 5h (ca.…”

Section: Resultsmentioning

confidence: 99%

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

Camoutsis

Geronikaki

Ćirić

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Bacterial infections have increased dramatically in recent years. Bacteria have been the cause of some of the most deadly diseases and widespread epidemics in human civilization.1) Moreover, the widespread use and misuse of antibiotics has caused bacterial resistance. Some of these resistant strains, such as vancomycin-resistant enterococci (VRE) and multidrug resistant Staphylococcus aureus (MRSA), are capable of surviving the effects of most, if not all, antibiotics currently in use. [2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria. 14)Thiadiazoles belong to the wider category of imidazole and triazole synthetic antifungal drugs which are designed to inhibit the enzyme cytochrome P450 14a-demethylase and inhibit the conversion of lanosterol to ergosterol, which is required in fungal cell membrane synthesis.1,3,4-Thiadiazoles are known to possess antibacterial and antifungal properties similar to those of well known sulphonamide drugs.15) Thus, the 1,3,4-thiadiazoles exhibit a broad spectrum of biological activities possibly due to the presence of the toxophoric -N-C-S moiety.16) Prompted by these observations and in continuation of our search for bioactive molecules, we designed the synthesis of a series of novel sulfonamide-1,3,4-thiadiazoles, emphasizing, in particular, on the strategy of combining two chemically different but pharmacologically compatible molecules (the sulfonamide nucleus and the five member heterocycle) in one frame, in order to study their antibacterial and antifungal activities.Chemistry The synthetic pathway followed for the preparation of the title compounds was accomplished as shown in Chart 1.Starting from ethyl(2-chlorosulfonyl-4,5-dimethoxyphenyl)acetate (1) 17,18) by reaction with secondary aliphatic amines in anhydrous benzene the corresponding sulfonamides Results and DiscussionBiological Evaluation and Lipophilicity Studies The results of antibacterial and antifungal activity of compounds 5a-m against a panel of selected Gram positive, Gram negative bacteria and fungi are presented in Tables 1 and 2 in comparison with those of the reference drugs ampicillin and streptomycin, bifonazole and ketoconazole respectively.Results of antibacterial activity of compounds (Table 1) show that the minimum inhibitory concentration (MIC) of compounds varies in the range of 0.92-4.6ϫ10 Ϫ2 mmol/ml, while minimum bactericidal concentration (MBC) varies between 1. 75-9.20ϫ10 Ϫ2 mmol/ml. Compounds 5a, 5b, 5c and 5g showed the lowest antibacterial activity among the tested compounds with 5a being t...

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“…This information is derived using a combination of DSC, solid-state NMR, Raman spectroscopy, and X-ray diffraction as well as MD experiments. This effect is related to their drug efficacy as it is reported in our previous study comparing the interdigitation effect in DPPC bilayers using a commercial potent AT 1 antagonist losartan and a synthetic derivative of low-activity MMK3 [(5S)-1-benzylo-5-(1H-benzimidazol-1-ylo-methylo)-2-pyrrolidinone] [19,22,39].…”

Section: Resultsmentioning

confidence: 74%

Partial interdigitation of lipid bilayers

Mavromoustakos

Chatzigeorgiou

Koukoulitsa

et al. 2011

Int J of Quantum Chemistry

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A methodology has been developed to detect partial interdigitation of lipid bilayers when a bioactive molecule is intercalated between the polar, interface, or hydrophobic segments. This methodology uses the easily accessible differential scanning calorimetry (DSC) technique as a screening one and the increase of DH due to the incorporated drug in lipid bilayers as a diagnostic thermodynamic parameter. The combined use of X-ray diffraction and Raman spectroscopy complement and confirm the provided by DSC information as it is shown in three classes of molecules, namely AT 1 antagonists, vinca alkaloids, and anesthetic steroids. For the two classes of molecules, AT 1 antagonists and vinca alkaloids, their presence in lipid bilayers results in the increase of DH and it is accompanied by the increase of trans:gauche ratio and the decrease of d-spacing as depicted by Raman spectroscopy and small-angle X-ray diffraction correspondingly, confirming the predictive ability of DSC experiments. When an anesthetic steroid is incorporated in lipid bilayers, neither increase of DH nor decrease of d-spacing was observed, confirming again the DSC results that show the absence of partial interdigitation of this class of molecules. Molecular dynamics simulations have been carried out for a representative system [(5S)-1-benzylo-5-(1H-benzimidazol-1-ylo-methylo)-2-pyrrolidinone (MMK3) ligands at 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer], and the results confirmed the experimental findings. The change of distance at z-axis of oxygen atoms at head group of lipid molecule has been measured throughout the simulations. Statistical analysis has shown $8.8 Å interdigitation. Derived computational results are encouraging and can be performed to another ligand/lipid system. The development of a theoretical methodology will lead to advance the field and save a valuable time and effort.

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Losartan’s molecular basis of interaction with membranes and AT1 receptor

Cited by 51 publications

References 29 publications

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

Partial interdigitation of lipid bilayers

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