Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use (64Cu/68Ga-DOTATATE, 68Ga-DOTATOC, 64Cu-SARTATE) and some in clinical development (68Ga-DOTANOC, 64Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2

Computational investigation of interaction of several antiinflammatory and anti-hypertensive drug molecules with individual DNA nucleobases and their base pairs by several DFT and QM/MM MD methods

This thesis investigates the interactions of various selected antiinflammatory and anti-hypertensive drug molecules with DNA nucleobases and their base pairs using the DFT and QM/MM MD computational chemistry methods. Firstly, the comparison with the CCSD(T) results revealed that the ωB97 family (ωB97X-D, ωB97M-V, and ωB97X-V) are the best methods for drug- DNA interactions. The ωB97X-D calculations indicated that the most negative binding energy among the drug-single base complexes is between celiprolol and guanine. However, evaluation of interaction energy alone is insufficient to understand drug-nucleobase interaction. When the effects of drug molecules on hydrogen bonds were examined in terms of angle and distance the DFT calculations point out that mefenamic acid and oxaprozin are the two drugs interacting effectively with both A-T and G-C base pairs. The molecular electrostatic potential (MEP) maps were determined for the drugs and nucleobases and it has been shown that they provide insight into explaining the donor-acceptor relationship and shed light on potential interactions. In addition, QM/MM MD calculations were performed on interactions of mefenamic acid and oxaprozin with DNA in the aqueous medium. The model quantum calculations (DFT) revealed that mefenamic acid gives interaction with nucleobase pairs through the carboxylic group, as did the QM/MM MD calculations. Hence, the DFT methods employed here for non-bonded interactions can be said to be rather reliable.Bu tez, seçilmiş çeşitli anti-inflamatuar ve anti-hipertansif ilaç moleküllerinin DNA nükleobazları ve baz çiftleri ile etkileşimlerini DFT ve QM/MM MD hesaplamalı kimya yöntemlerini kullanarak araştırmaktadır. İlk olarak, CCSD(T) sonuçlarıyla yapılan karşılaştırma, ωB97 ailesinin (ωB97X-D, ωB97M-V ve ωB97X-V) ilaç-DNA etkileşimleri için en iyi yöntemler olduğunu ortaya koydu. ωB97X-D hesaplamaları, ilaç-tek baz kompleksleri arasında en negatif bağlanma enerjisinin celiprolol ve guanin arasında olduğunu göstermiştir. Bununla birlikte, tek başına etkileşim enerjisinin değerlendirilmesi, ilaç-nükleobaz etkileşimini anlamak için yetersizdir. İlaç moleküllerinin hidrojen bağları üzerindeki etkileri açı ve mesafe açısından incelendiğinde, DFT hesaplamaları mefenamik asit ve oksaprozinin hem A-T hem de G-C baz çiftleri ile etkili bir şekilde etkileşen iki ilaç olduğuna işaret etmektedir. İlaçlar ve nükleobazlar için moleküler elektrostatik potansiyel (MEP) haritaları belirlenmiş ve bunların donör-alıcı ilişkisini açıklamada içgörü sağladıkları ve potansiyel etkileşimlere ışık tuttuğu gösterilmiştir. Ayrıca mefenamik asit ve oksaprozinin sulu ortamda DNA ile etkileşimleri üzerinde QM/MM MD hesaplamaları yapıldı. Model kuantum hesaplamaları (DFT), mefenamik asidin, QM/MM MD hesaplamalarında olduğu gibi, karboksilik grup aracılığıyla nükleobaz çiftleri ile etkileşim sağladığını ortaya çıkardı. Bu nedenle, burada bağlı olmayan etkileşimler için kullanılan DFT yöntemlerinin oldukça güvenilir olduğu söylenebilir

Determination of Gluconate Binding Properties on Magnetite Surface and Investigation of Carboxymethylation and Hydrazination Mechanisms of the Gluconated Magnetite Surface: A Computational Study

In the present study, the probable binding structure of a gluconate molecule with magnetite, (Fe3O4) nanoparticles, as well as, carboxymethylation and hydrazination mechanisms of the gluconate bound to the iron oxide surface have been computationally investigated by the DFT-B3LYP method. The B3LYP/LanL2DZ calculations together with experimental IR data available revealed that the probable binding structure of gluconate is bidentate bridged binding to the magnetite surface. The carboxymethylation and hydrazination mechanisms of gluconate were calculated at B3LYP/6- 31+G(d,p) level of theory. The results indicate that the reaction between gluconate and chloroacetate in aqueous medium has one step mechanism passing through a low activation barrier (12.3 kcal/mol) with a reaction enthalpy of –42.8 kcal/mol. In addition, hydrazone bond formation reaction of the gluconate bound to the iron oxide surface has a highly-exothermic two-step-mechanism with barriers of 7.1 and 2.4 kcal/mol, respectively, in water. The activation barrier of the overall reaction is accepted as the barrier of the first step since the barrier of this step is greater than that of the second one. Consequently, it can be predicted that both carboxymethylation and hydrazination reactions should be spontaneous under moderate conditions

Association of Acromegaly and Multiple Myeloma: A Case Report

Malignancy is an important cause of mortality in acromegaly. Hematological malignancies are very rare in acromegaly. Here, we report an 80-yearold patient with acromegaly and multiple myeloma. Patient died within a month of diagnosis. Previous studies have shown that growth hormone and somatomedin-C activate B lymphocyte and somatomedin-C receptors are found in multiple myeloma cells. Possible effects of growth hormone and somatomedin-C on multiple myeloma progression are discussed in the light of the relevant literature.Akromegali hastalarında malignite önemli bir mortalite nedenidir. Hematolojik maligniteler akromegali hastalarında oldukça nadiridir. Burada eş zamanlı akromegali ve multiple myeloma tanısı konulan 80 yaşında bir olgu sunuldu. Olgu tanıdan sonraki bir ay içinde kaybedildi. Büyüme hormonu ve somatomedin-C ‘nin B lenfositleri aktive ettiği ve somotomedin-C reseptörlerinin multiple myeloma hücrelerinde bulunduğu daha önceden gösterilmiştir. Büyüme hormonu ve somatomedin-C ‘nin myeloma progresyonu üzerine olan bu olası etkileri literatür eşliğinde tartışıldı

Akromegali ve multiple myeloma birlikteliǧi: Bir olgu sunumu

Malignancy is an important cause of mortality in acromegaly. Hematological malignancies are very rare in acromegaly. Here, we report an 80-yearold patient with acromegaly and multiple myeloma. Patient died within a month of diagnosis. Previous studies have shown that growth hormone and somatomedin-C activate B lymphocyte and somatomedin-C receptors are found in multiple myeloma cells. Possible effects of growth hormone and somatomedin-C on multiple myeloma progression are discussed in the light of the relevant literature.Akromegali hastalarında malignite önemli bir mortalite nedenidir. Hematolojik maligniteler akromegali hastalarında oldukça nadiridir. Burada eş zamanlı akromegali ve multiple myeloma tanısı konulan 80 yaşında bir olgu sunuldu. Olgu tanıdan sonraki bir ay içinde kaybedildi. Büyüme hormonu ve somatomedin-C ‘nin B lenfositleri aktive ettiği ve somotomedin-C reseptörlerinin multiple myeloma hücrelerinde bulunduğu daha önceden gösterilmiştir. Büyüme hormonu ve somatomedin-C ‘nin myeloma progresyonu üzerine olan bu olası etkileri literatür eşliğinde tartışıldı