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1

Witaminy z grupy B : opis właściwości fizykochemicznych oraz bioaktywności z wykorzystaniem przykładowych narzędzi cheminformatycznych

Banach Sylwia, Jezierska Aneta

Wiadomości Chemiczne

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2023

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[Z] 77, 9-10

873--896

EN

This paper presents a literature review of the biochemistry of vitamins B and the results of in silico physicochemical properties and bioactivity studies. The description was performed by cheminformatics tools closely related to the field of Medicinal Chemistry. It allows us to predict a great number of properties e.g. logP, TPSA, molecular volume or bioactivity associated with the chosen proteins (like kinases, proteases etc.). These investigations were carried out with the use of cheminformatics web tool Molinspiration. Its great advantages are mainly its wide availability, ease of application and quick analysis of small compounds. Thanks to the comparison with literature data of well–known B vitamins, it is possible to confirm that current cheminformatic web tools provide high reliability of the results and can support Drug Design methods.

2

Natural products as potential inhibitors of FLT3 for acute myeloid leukemia: HTVS, docking, and molecular dynamic simulation

Salah Salsabeel, Sami Najat, Ali Sarah, Khalid Teemah-Alrahman, Alnajjar Radwan

Scientiae Radices

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2023

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Vol. 2, Iss. 4

325--346

EN

Cancer is one the most common health issues worldwide, with cancer-related mortality of 9.5 million in 2018, with an expectation to become 29.5 by 2040. Among others, acute myeloid leukemia (AML) is common among older people. FLT3 mutations are one of the most common genetic aberrations found in Acute Myeloid Leukemia and are associated with poor prognosis. Herein, we attempt to identify natural compounds as potential candidates to treat AML by targeting the FLT3 kinase domain using in silico approaches. The COCONUT database, which contains 407,270 natural compounds, was HTVS against the FLT3 kinase domain active site, and promising compounds were subject to molecular docking. Finally, frontier compounds were validated further using molecular dynamic simulation. In total, ten compounds were identified with docking scores higher than Quizartinib (-11.606 kcal/mol), with the best three compounds showing a docking score of -18.052, -15.772, and -16.767 kcal, respectively, and compound 2 showing excellent stability in molecular dynamic simulation.

3

Estimation of lipophilicity and design of new 17β-carboxamide glucocorticoids using RP-HPLC and quantitative structure-retention relationships analysis

Dobričić Vladimir, Bošković Jelena, Vukadinović Dragana, Vladimirov Sote, Čudina Olivera

Acta Chromatographica

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2022

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Vol. 34, no. 2

130--137

EN

Eight 17β-carboxamide glucocorticoids with local anti-inflammatory activity were selected and their retention behavior tested in six RP-HPLC systems (I–VI). logkw, a, and φ 0 parameters were calculated and correlation with previously determined logPo/w values was examined. RP-HPLC system IV, which consisted of cyano column and methanol–water mobile phases (50:50, 60:40, 70:30, and 80:20, v/v), was selected as the most reliable for lipophilicity prediction and used for the analysis of chromatographic behavior of remaining fourteen 17β-carboxamide glucocorticoids. Quantitative structure-retention relationships analysis was performed and PLS(logkw) model was selected as the most statistically significant. On the basis of selected model and interpretation of corresponding descriptors, new derivatives with higher logkw values and higher expected lipophilicity were designed.

4

Investigation of interactions between dermorphin analogs and µ-opioid receptor

Karczyńska A., Zaborowski B., Ślusarz M.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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2014

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Vol. 18, No 4

331--336

EN

Opioid receptors play the pain control function in the body. Most of the research is carried out to find the most effective analgesic. The earliest analgesic i s morphine, however, unfortunately it has many side effects [Mizoguchi H et al. 2003 J. Pharmacol Sci. 93 423]. At a later time dermorphin was discovered as another potent analgesic [Mont ecucchi P C et al. 1981 Int. J. Pept. Protein Res. 17 275]. Unfortunately, this peptide is not resistant to enzymatic metabolism [Kisara K et al. 1986 Br. J. Pharmacol. 87 183; Sasaki Y et al. 1985 Neuropeptides 5 391]. The objective of this study is to search for new opioid analgesics by in vestigation of interactions between dermorphin analogs and the μ -opioid receptor using molecular modeling methods. MOPR ( μ -Opioid Peptide Receptor) complexes with several ligands (with kno wn biological activity) were modeled to explain how the structure of the complex was related to the biological activity. The investigated dermorphin analogs containing [ DMT 1 , D -Arg 2 ] (especially tetrapeptides) may become a good alternative for the currently used an algesics.

5

On the computational complexity of designing DNA randomizations in a combinatorial protein experiment

Błażewicz J., Dziurdza B., Markiewicz W. T., Oguz C.

Foundations of Computing and Decision Sciences

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2007

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Vol. 32, No. 3

185-197

EN

In combinatorial protein experiments based on phage display and similar methods, protein libraries are constructed by expressing a partially randomized DNA (gene) libraries. Since the distribution of proteins in the output library depends on nucleotides frequencies in DNA library one has to adjust them carefully taking into account diversity-completeness trade-off and results from possible previous cycles of experiments (i.e. knowledge about sequences that have been already obtained and tested). The approach considered in this paper allows to maximize the number of new amino acid sequences physically generated in each cycle of the experiment. The mathematical model of the described approach is presented and its computational complexity is analyzed.

6

An approach to protein folding on the grid – EuChinaGRID experience

Malawski M., Szepieniec T., Kochanczyk M., Piwowar M., Roterman I.

Bio-Algorithms and Med-Systems

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2007

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Vol. 3, no. 5

45--49

EN

Contemporary pharmacology in its quest for more relevant and effective drugs needs to examine large range of biological structures to identify biological active compounds. We consider large grid environment the only platform to face such a computational challenge. In our project, the search is focused on peptide-like molecules containing about 70 amino acids in a single polypeptide chain. The limited number of proteins existing in the nature will be extended to those, which have not been recognized in any organisms (“never born proteins”). The assumption is that those which do not exist in the nature may also render biological activity, which directed on pharmacological use may correct some pathological phenomena. As the function results from the structure, two approaches are applied to predict cartesian coordinates of proteins’ atoms: sophisticated Monte Carlo structure creation, elimination and refinement using the Rosetta program and our own program for simulation of the protein folding process. As a computing platform we use the EuChinaGRID project resources, which are currently a part of EGEE infrastructure and are expanding to include Chinese resources as well. We describe the approach for porting the application to the grid and the prototype portal developed for simulation management and results analysis.

7

Docker Analyzer: Program for comparison of docking results

Nielepiec A., Jurkowski W.

Bio-Algorithms and Med-Systems

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2006

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Vol. 2, no. 4

29--36

EN

Vast amount of docking algorithms and scoring functions available encourage development of methods aimed to adjust functionality of docking tools. A certain level of scoring functions precision is needed to recognize complexes of specific intermolecular interactions. Having this kind of model morę detailed blind prediction of molecular complexes would be possible. To enhance specificity of docking results tools unifying application of many scoring functions should be developed. A program for assessment of molecular docking: Docker Analyzer is presented as preliminary approach. Complex calculation of over ten scoring functions and its simultaneous use (multiple consensus scoring) is possible to improve default selection of best hits after standard molecular docking procedure.

PL

Dostępność wielu programów dokujących oraz różnorodność używanych w nich funkcji służących do oceny poprawności kompleksów białko-ligand skłania do ich oceny i porównań. Istotna wydaje się być możliwość dobrania funkcji oceniającej pod kątem specyfiki badanego układu, a więc wybór funkcji, która najpoprawniej w danych przypadku opisywałaby naturę oddziaływań międzycząsteczkowych. Takie podejście powinno pomóc w poprawnym dokowaniu w przypadku kiedy brak jest wstępnej informacji strukturalnej (np. przy nieznanym miejscu wiążącym). Praca ta przedstawia program do oceny efektywności procedur dokowania będący wstępną realizacją takiego podejścia. Program Docker Analyzer umożliwia jednoczesne obliczenie kilkunastu popularnych funkcji oceniających i ich wzajemne porównanie, wyznaczenie na ich podstawie wskaźnika konsensusowego oraz prostą wizualizację kompleksów.

8

Electrostatics in computer-aided drug design

Naray-Szabo G., Matyus P.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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1998

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Vol. 2, No 4

551-562

EN

Hydrogen bonds and charge-charge interactions, determined by molecular electrostatics, play essential role in biopolymer-ligand associations. Accordingly, electrostatics is crucial in the qualitative and quantitative characterisation of the binding of drugs to their target molecules. In the following, we will give an account on the role of molecular electrostatics in a drug design, laying emphasis on our own work. We will survey the most important computation methods of molecular electrostatic potentials, then outline basic aspects of molecular recognition: steric, electrostatic and hydrophobic complementarity. On the basis of the complementarity, we will also define molecular similarity and discuss various applications of these concepts to the treatment of protein-ligand interactions and a rational drug design. Special attention will be paid to a receptor mapping and to a comparative molecular field analysis, with some our recent applications. A further important point will be the molecular electrostatic field (potential gradient) as a hydrophobicity measure. We will argue that the hydrophobic complementarity and similarity can be treated on the basis of matching regions of the interacting molecules that are characterised by a similar magnitude of the electrostatic field. The concept of the electrostatic complementarity will be extended to enzyme-substrate interactions, providing a firm basis for the quantitative estimation of catalytic rate enhancement.