Rational Design of Selective Industrial Performance Chemicals Based on Molecular Modeling Computations

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

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Multilevel Molecular Modeling Approach for a Rational Design of Ionic Current Sensors for Nanofluidics

Journal of Chemical Theory and Computation ◽

10.1021/acs.jctc.8b00073 ◽

2018 ◽

Vol 14 (6) ◽

pp. 3113-3120 ◽

Cited By ~ 2

Author(s):

Alexsandro Kirch ◽

James M. de Almeida ◽

Caetano R. Miranda

Keyword(s):

Molecular Modeling ◽

Rational Design ◽

Ionic Current ◽

Modeling Approach ◽

Current Sensors

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Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

International Journal of Molecular Sciences ◽

10.3390/ijms21010214 ◽

2019 ◽

Vol 21 (1) ◽

pp. 214

Author(s):

Yuliya V. Sherstyuk ◽

Nikita V. Ivanisenko ◽

Alexandra L. Zakharenko ◽

Maria V. Sukhanova ◽

Roman Y. Peshkov ◽

...

Keyword(s):

Molecular Modeling ◽

Binding Site ◽

Rational Design ◽

In Silico Analysis ◽

Parp Inhibition ◽

High Yield ◽

Design Synthesis ◽

Molecular Modeling Study ◽

Parp 1 ◽

Modeling Study

We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors.

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