Fig 4 - uploaded by Neaz Morshed
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Electron density ( solid surface ) and electrostatics potential ( mesh ) density map for a lowest energy conformer, b highest energy conformer, c docked conformer for the ligand 14
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Abnormal expression of cyclin-dependent kinase 2 (CDK2)/cyclin-E is detected in colorectal, ovarian, breast and prostate cancers. The study of CDK2 with a bound inhibitor revealed CDK2 as a potential therapeutic target for several proliferative diseases. Several highly selective inhibitors of CDK2 are currently undergoing clinical trials, but possi...
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... charge and electron density maps for different conformers of the most active molecule (compound 14 ), as determined by the DFT/MM method, are illustrated in Fig. 4a – c. The differences between these three electron density maps gave a direct indication of charge migration due to polarization. Therefore, we could determine the change in the electron density and electrostatic potential of each inhibitor for different conformations within the protein. The electron density (cage) and electrostatic potential (surface) maps for representative structures are shown in Fig. 4. As we can see in Fig. 4a and c, the electrostatic potential distribution is similar (bluish in color) and the potential ranges were set as 43 and 45 kcal mol -1 , while the map in Fig. 4b (high energy conformer) is red in color, which indicates a rather negative potential; the range was set as 49 kcal mol -1 . The electron density maps were similar in all three conformations except for the zone between SO 2 and the carbonyl oxygen atom. This particular zone was most neutral in docked conformation as shown by the white surface in Fig. 4c. Even though both the oxygen atoms have lone pair of electrons and the sulfur atom also has a lone pair of electrons, the low electron density around these region indicates that their bulk might contribute to a steric interaction rather than an electrostatic ...
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Citations
... Over 50 CDK inhibitors have been described [102,103]; however, most exploit the ATPbinding domain and remain relatively nonselective, although newer agents have recently shown enhanced specificity for cyclin E or A [104]. Synthetic sulfonamides, such as E7070, had shown promising preclinical activity, but development did not progress beyond Phase II [105]. ...
Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.
A series of pyrazolo[3,4-d]pyrimidin-4-one scaffold were designed and synthesized as novel CDK2 inhibitors. By analyzing the common motifs of various known inhibitors, the designed compounds 1 were virtually screen for their inhibitory activity by docking into the active pocket of CDK2. The influence of different substitutes on the docking results was investigated. A total of 15 pyrazolo[3,4-d]pyrimidin-4-ones 1 were synthesized by Paal-Knorr reaction, pyrimidine ring closure, bromination, Suzuki coupling reaction, amide formation and Knoevenagel condensation. The Cell Counting Kit-8 (CCK-8) was used to evaluate the inhibitory activity of pyrazolo[3,4-d]pyrimidin-4-ones 1 in the breast cancer cell line MCF-7 in vitro using Etoposide as a reference control substance. The screening results demonstrated that the designed compounds have significant antiproliferative activity, and compounds 1e and 1j were the most active compounds with IC50 values of 10.79 μM and 10.88 μM, respectively, being better than that of Etoposide (IC50 = 18.75 μM). The enzyme inhibition assay was carried out against CDK2, the results indicated that the compounds 1e and 1j significantly inhibited CDK2 with IC50 values of 1.71 μM and 1.60 μM.
Quantum mechanics (QM) methods provide a fine description of receptor-ligand interactions and of chemical reactions. Their use in drug design and drug discovery is increasing, especially for complex systems including metal ions in the binding sites, for the design of highly selective inhibitors, for the optimization of bi-specific compounds, to understand enzymatic reactions, and for the study of covalent ligands and prodrugs. They are also used for generating molecular descriptors for predictive QSAR/QSPR models and for the parameterization of force fields. Thanks to the continuous increase of computational power offered by GPUs and to the development of sophisticated algorithms, QM methods are becoming part of the standard tools used in computer-aided drug design (CADD). We present the most used QM methods and software packages, and we discuss recent representative applications in drug design and drug discovery.
Oxindolimine-copper(II) and zinc(II) complexes that previously have shown to induce apoptosis, with DNA and mitochondria as main targets, exhibit here significant inhibition of kinase CDK1/cyclin B protein. Copper species are more active than the corresponding zinc, and the free ligand shows to be less active, indicating a major influence of coordination in the process, and a further modulation by the coordinated ligand. Molecular docking and classical molecular dynamics provide a better understanding of the effectiveness and kinase inhibition mechanism by these compounds, showing that the metal complex provides a stronger interaction than the free ligand with the ATP-binding site. The metal ion introduces charge in the oxindole species, giving it a more rigid conformation that then becomes more effective in its interactions with the protein active site. Analogous experiments resulted in no significant effect regarding phosphatase inhibition. These results can explain the cytotoxicity of these metal complexes towards different tumor cells, in addition to its capability of binding to DNA, and decreasing membrane potential of mitochondria.
Graphical Abstract
A major objective of theoretical and computational chemistry is the calculation of the energy and properties of molecules, so that chemical reactivity and material properties can be understood from first principles. The most accurate methods available today, which directly solve this equation for molecules, can only be applied to a very small subset of chemical problems. One approach that deals with the poor scaling of quantum mechanical methods with system size is not to treat the entire system with quantum mechanical methods. Often one is not interested in a detailed and highly accurate quantum mechanical treatment of the entire system, but rather a selected much smaller region of the system, for example, an active site in an enzyme.
