183 research outputs found

    A Comparative Molecular Dynamics, MM−PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV‑1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants

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    A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug–protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug’s binding affinity, as shown by MM–PBSA and thermodynamic integration (TI) calculations (ΔΔGTI = 0.3 kcal/mol; ΔΔGMM–PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR

    Η Σημειολογία των αριθμών και των ωρών στο Κατά Ιωάννη Ευαγγέλιο

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    Στην παρούσα διδακτορική διατριβή διαπραγματεύεται η σημειολογία των αριθμών και ωρών που απαντούν στο Κατά Ιωάννη Ευαγγέλιο. Οι ερμηνείες οι οποίες καταγράφονται περιλαμβάνουν Πατέρες και Εκκλησιαστικούς συγγραφείς κατά προτεραιότητα της Ορθόδοξης Πίστης μας και δευτερευόντως άλλων δογμάτων. Επιπρόσθετα, συγκαταλέγονται οι ερμηνείες σύγχρονων Ελλήνων ερμηνευτών θεολόγων και της αλλοδαπής. Στόχος της διδακτορικής διατριβής είναι να εγκαθιδρυθεί μία συστηματική ανάλυση και μεθοδολογία στην ερμηνεία των αριθμών και ωρών η οποία πιθανόν να έχει προεκτάσεις και στην υπόλοιπο Αγία Γραφή. Πράγματι, τα συμπεράσματα τα οποία εξήχθησαν μπορούν να έχουν εφαρμογή κυρίως στα Καινοδιαθηκικά κείμενα αλλά ακόμη και σε κείμενα της Παλαιάς Διαθήκης. Τα κείμενα της Αγίας Γραφής προσφέρονται για πλουραλισμό ερμηνειών φτάνει αυτές να μην παρεκκλίνουν από το Χριστιανικό δόγμα και να μην οδηγούν σε πολυθεϊκές ή αντιθεϊκές ερμηνείες. Πιστεύουμε ότι τα συμπεράσματα τα οποία προέκυψαν σε κάθε εδάφιο το οποίο περιέχει αριθμό ή ώρα είναι σημαντικά. Ο πλουραλισμός σε αλληγορικές και μη ερμηνείες βοηθά στην κατανόηση της Αγιοπνευματικής ποικιλότητας, στον φωτισμό ανάλογα με το πνευματικό υπόβαθρο του μελετητή. Παρέχει επίσης ευδαιμονία και αγαλλίαση στον Πιστό γιατί κατανοεί ότι η Αγία Γραφή προσφέρεται ως πνευματική κλίμακα ανέλιξης με αμέτρητα σκαλοπάτια. Οι ανάλογες ερμηνείες βοηθούν τον Πιστό να ανελιχθεί στην πνευματική κλίμακα. Τέλος, θα πρέπει να σημειωθεί ότι σε πολλά εδάφια δόθησαν νέες ερμηνείες με βάση τα σύγχρονα δεδομένα τα οποία έφερε στο φως η επιστημονική γνώση. Αυτές οι νέες ερμηνείες δεν έρχονται σε αντίφαση ή ακυρώνουν αυτές των Αγίων Πατέρων της Ορθόδοξης Πίστης μας αλλά αντίθετα τις συμπληρώνουν.In this PhD dissertation, the semiology of the numbers and hours met in the Gospel of John is discussed. The interpretations recorded include Fathers and Ecclesiastical Writers as a priority of our Orthodox Faith and, secondarily, other doctrines. In addition, interpretations of contemporary theologians and the non-Greek are included. The aim of the PhD thesis is to establish a systematic analysis and methodology in interpreting the numbers and hours found in John Gosple which may have implication for the rest of the Bible as well. Indeed, the conclusions that have been excerpted can apply mainly to the New Testament texts, but even to texts in the Old Testament. The Bible texts lend themselves to pluralism of interpretations as far as they do not deviate form the Christian doctrine and lead to polytheic or antitheic interpretations. We believe that the conclusions that came out in each chapter containing a number or hour are important. Pluralism in allegorical and non-interpretations helps to understand the Spiritual diversity in lighting according to the scholar’s spiritual background. Finally, it should be noted that in many passages, new interpretations have been given on the basis of the modern data brought to light by scientific knowledge. These new interpretations do not contradict or invalidate those of the Holy Fathers of our Orthodox Faith but instead supplement them

    Interactions of the dipeptide paralysin β-Ala-Tyr and the aminoacid Glu with phospholipid bilayers

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    AbstractExisting evidence points out that the biological activity of β-Ala-Tyr may in part related to its interactions with the cell membranes. For comparative reasons the effects of Glu were also examined using identical techniques and conditions. In order to examine their thermal and dynamic effects on membrane bilayers a combination of DSC, Raman and solid state NMR spectroscopy on DPPC/water model membranes were applied and the results were compared. DSC data showed that Glu perturbs to a greater degree the model membrane compared to β-Ala-Tyr. Thus, alteration of the phase transition temperature and half width of the peaks, abolishment of the pretransition and influence on the enthalpy of the phase transition were more pronounced in the Glu loaded bilayers. Raman spectroscopy showed that incorporation of Glu in DPPC/water bilayers increased the order in the bilayers in contrast to the effect of the dipeptide. Several structural and dynamical properties of the DPPC multilamellar bilayers with and without the dipeptide or Glu were compared using high resolution C-13 MAS (Magic Angle Spinning) spectra and spectral simulations of inhomogeneously broadened, stationary P-31 NMR lineshapes measured under CP (Cross-polarization) conditions. These methods revealed that the aminoacid Glu binds in the close realm of the phosphate in the hydrophilic headgroup of DPPC while β-Ala-Tyr is located more deeply inside the hydrophobic zone of the bilayer. The P-31 NMR simulations indicated restricted fast rotary motion of the phospholipids about their long axes in the organized bilayer structure. Finally, by the applied methodologies it is concluded that the two molecules under study exert dissimilar thermal and dynamic effects on lipid bilayers, the Glu improving significantly the packing of the lipids in contrast to the smaller and opposite effect of the dipeptide

    The conformation of (-)-8α- and (-)-8α-hydroxy-Δ9-tetrahydrocannabinols and their interactions with model membranes.

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    8α- and 8β-Hydroxy-δ9-tetrahydrocannabinols (THC's), two metabolites of the naturally occurring δ9-THC have been shown to possess differences in pharmacological activity. We have studied the conformations of these two compounds, as well as their interactions with model membrane systems and compared them with δ9-THC. The conformational study, carried out in solution and using high resolution NMR indicated that differences in the ring conformations of these two compounds were negligible butthat the 8-hydroxy group of the 8β-OH compound extended approximately 1.4Å higher above the plane of the aromatic ring than in the 8α-OH isomer. This difference could prove significant in the interaction of these molecules with lipid bilayers. We found that both 8α- and 8β-OH analogs affected the melting behavior of hydrated DPPC bilayers including a lowering of the main transition temperature (Tc), a broadening of that transition and the abolishment of the pretransition of DPPC. The effects of the more active compound, 8β-OH-δ9-THC on the model membrane approximated closely those of δ9-THC, while the less active 8α-OH epimer produced different thermotropic changes

    Small Peptides Able to Suppress Prostaglandin E₂ Generation in Renal Mesangial Cells.

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    Peptide drug discovery may play a key role in the identification of novel medicinal agents. Here, we present the development of novel small peptides able to suppress the production of PGE₂ in mesangial cells. The new compounds were generated by structural alterations applied on GK115, a novel inhibitor of secreted phospholipase A₂, which has been previously shown to reduce PGE₂ synthesis in rat renal mesangial cells. Among the synthesized compounds, the tripeptide derivative 11 exhibited a nice dose-dependent suppression of PGE₂ production, similar to that observed for GK115

    Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode

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    An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A2A and A1ARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinder library of 14400 compounds was utilized to apply a combination of structure-based against the crystal structure of A2AAR and ligand-based methodologies. The docking poses were rescored by CHARMM energy minimization and calculation of the desolvation energy using Poisson-Boltzmann equation electrostatics. Out of the eight selected and tested compounds, five were found positive hits (63% success). Although the project was initially focused on targeting A2AAR, the identified antagonists exhibited low micromolar or micromolar affinity against A2A/A3, ARs, or A3AR, respectively. Based on these results, 19 compounds characterized by novel chemotypes were purchased and tested. Sixteen of them were identified as AR antagonists with affinity toward combinations of the AR family isoforms (A2A/A3, A1/A3, A1/A2A/A3, and A3). The second part of this work involves the performance of hundreds of molecular dynamics (MD) simulations of complexes between the ARs and a total of 27 ligands to resolve the binding interactions of the active compounds, which were not achieved by docking calculations alone. This computational work allowed the prediction of stable and unstable complexes which agree with the experimental results of potent and inactive compounds, respectively. Of particular interest is that the 2-amino-thiophene-3-carboxamides, 3-acylamino-5-aryl-thiophene-2-carboxamides, and carbonyloxycarboximidamide derivatives were found to be selective and possess a micromolar to low micromolar affinity for the A3 receptor

    Conformational analysis of AT1 antagonist valsartan using 2DNMR spectroscopy and computational analysis: determination of thermodynamic parameters through dynamic NMR spectroscopy and semi-empirical calculations

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    AbstractArticles published in this journal are Indexed or Abstracted in Chemical Abstracts, Elsevier's Bibliographic Databases: Scopus, EMBASE, EMBiology, Elsevier BIOBASE, Compendex, GEOBASE, FLUIDEX, TEXTILE

    From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBS): Perspectives of ARBs in COVID-19 Therapy

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    The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the active conformation. These studies on angiotensin II led to the discovery of Sarmesin, a type II angiotensin II antagonist, and the breakthrough non-peptide mimetic Losartan, the first in a series of sartans marketed as a new generation of anti-hypertensive drugs in the 1990s. Angiotensin II receptor blockers (ARBS) and angiotensin I converting enzyme inhibitors (ACEI) were recently reported to protect hypertensive patients infected with SARS-CoV-2. The renin–angiotensin system (RAS) inhibitors reduce excess angiotensin II and increase antagonist heptapeptides alamandine and aspamandine which counterbalance angiotensin II and maintain homeostasis and vasodilation
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