More compounds having this backbone with different functional groups should be designed with the aim of finding highly active CK2 inhibitors. Acknowledgments Marc Le Borgne, Christelle Marminon, Laurent Ettouati, and Zouhair Bouaziz thank Faten Alchab and Anthony Prandina for their assistance regarding the chemistry. CK2 enzyme using MOE and sorted according to their S score (energy-based scoring method implemented in MOE) to rank the best ligand in terms of the orientation and binding to the active site. The four tested compounds were selected and visual 2D and 3D inspections were carried out to exclude false positives due to assumptions and shortcomings in the docking methods and scoring function [42]. The active site was analyzed to determine the proteinCligand conversation to show exactly which atoms could interact. Physique 3 shows the 3D and 2D interactions of the four tested compounds and it is clear that they fit well in the ATP active site of CK2. The four docked compounds were inserted into the narrow ATP binding site of CK2 (Physique 3) and all of them were able to produce a C conversation between the aromatic ring of the naphtho[2,3-b]furan-4,9-dione and the side-chain residues of Ile174. Compound 01893208 was also able to produce direct bonding with Asp120 and Glu123. Compound 37867960 and compound 00082235 showed direct bonding with Lys68 and via a water molecule with Glu81. Compound 01236034 had direct bonding with Val53 and via a water molecule with Glu81 as well. Emodin in the crystal structure created a C conversation with Phe113 and direct bonding with Lys68. Open in a separate window Open in a separate window Physique 3 3D binding mode of the four tested compounds with the ATP binding site of CK2 with surface map (a,b) the 2D binding mode. (1) Compound 00082235; (2) Compound 01893208; (3) Compound 37867960, (4) Compound 01236034. Several studies have been performed to develop an active CK2 inhibitor using different in silico techniques [23]; however, few ligand-based drug design (LBDD) techniques were able to put forward a successful candidate [23]. Our database of indeno[1,2- em b /em ]indoles was not only used to find a list of candidates via a pharmacophore approach, but also exploited to develop a new reliable QSAR model, which we used to predict the activity of these compounds. We exhibited that some of the tested naphtho[2,3- em b /em ]furan-4,9-dione compounds were active using both in vitro evaluation and cellular assays. Nevertheless, we were not able to correlate our predicted IC50 values to the tested IC50 values of naphtho[2,3- em b /em ]furan-4,9-dione compounds since only four compounds were available to us. As a matter of fact, the moderate inhibitory activity of some tested naphtho[2,3- em b /em ]furan-4,9-dione derivatives was not a surprise for us, as a variation between predicted and tested inhibition is usually expected in such QSAR studies. This was also the case in some compounds in the test set, where the r2 for the test set was 0.77. Unfortunately, it was not possible to correlate the predicted and tested values for all those naphtho[2,3- em b /em ]furan-4,9-dione derivatives presented in this study, since only four of them were tested. It is important to highlight that the aim of this work was to describe the inhibitory activity of 20 novel indeno[1,2- em b /em ]indoles and to show that compounds with naphtho[2,3- em b /em ]furan-4,9-dione backbone were appropriate for developing CK2 inhibitors, which was proved by compound 00082235. The future step will be optimizing this compound by synthesizing a series of compounds with different substituents on a naphtho[2,3- em b /em ]furan-4,9-dione backbone and performing a SAR study with the aim of finding a highly active CK2 inhibitor. 3. Materials and Methods 3.1. Chemistry All indeno[1,2- em b /em ]indole derivatives 1C30 used in this study were synthesized by us. The procedures for the synthesis of indeno[1,2- em b /em ]indoles have already been described for compounds 4e [35], 4f [35], 4g [17], 4v [35], 4x [16], 4y [16], 5d [17], 5j [16], 5k [16], and 6g [16]. For the compounds 4d, 4hCj, 4pCs, 4w, 5a, 5c, 5f, 5h, 5g, and 6aCf, the chemistry is usually described in the Supporting Information (Files S1 and S2). Four naphtho[2,3- em b /em ]furan-4,9-dione derivatives were purchased from.The structure was optimized by using the QuickPrep function implemented in the MOE software. orientation and binding to the active site. The four tested compounds were selected and visual 2D and 3D inspections were carried out to exclude false positives due to assumptions and shortcomings in the docking methods and scoring Rabbit Polyclonal to CDH11 function [42]. The active site was analyzed to determine the proteinCligand interaction to show exactly which atoms could interact. Figure 3 shows the 3D and 2D interactions of the four tested compounds and it is clear that they fit well in the ATP active site of CK2. The four docked compounds were inserted into the narrow ATP binding site of CK2 (Figure 3) and all of them were able to create a C interaction between the aromatic ring of the naphtho[2,3-b]furan-4,9-dione and the side-chain residues of Ile174. Compound 01893208 was also able to create direct bonding with Asp120 and Glu123. Compound 37867960 and compound 00082235 showed direct bonding with Lys68 and via a water molecule with Glu81. Compound 01236034 had direct bonding with Val53 and via a water molecule with Glu81 as well. Emodin in the crystal structure created a C interaction with Phe113 and direct bonding with Lys68. Open in a separate window Open in a separate window Figure 3 3D binding mode of the four tested compounds with the ATP binding site of CK2 with surface map (a,b) the 2D binding mode. (1) Compound 00082235; (2) Compound 01893208; (3) Compound 37867960, (4) Compound 01236034. Several studies have been performed to develop an active CK2 inhibitor Ampiroxicam using different in silico techniques [23]; however, few ligand-based drug design (LBDD) techniques were able to put forward a successful candidate [23]. Our database of indeno[1,2- em b /em ]indoles was not only used to find a list of candidates via a pharmacophore approach, but also exploited to develop a new reliable QSAR model, which we used to predict the activity of these compounds. We demonstrated that some of the tested naphtho[2,3- em b /em ]furan-4,9-dione compounds were active using both in vitro evaluation and cellular assays. Nevertheless, we were not able to correlate our predicted IC50 values to the tested IC50 values of naphtho[2,3- em b /em ]furan-4,9-dione compounds since only four compounds were available to us. As a matter of fact, the moderate inhibitory activity of some tested naphtho[2,3- em b /em ]furan-4,9-dione derivatives was not a surprise for us, as a variation between predicted and tested inhibition is expected in such QSAR studies. This was also the case in some compounds in the test set, where the r2 for the test set was 0.77. Unfortunately, it was not possible to correlate the predicted and tested values for all naphtho[2,3- em b /em ]furan-4,9-dione derivatives presented in this study, since only four of them were tested. It is important to emphasize that the aim of this work was to describe the inhibitory activity of 20 novel indeno[1,2- em b /em ]indoles and to show that compounds with naphtho[2,3- em b /em ]furan-4,9-dione backbone were appropriate for developing CK2 inhibitors, which was proved by compound 00082235. The future step will be optimizing this compound by synthesizing a series of compounds with different substituents on a naphtho[2,3- em b /em ]furan-4,9-dione backbone and performing a SAR study with the aim of finding a highly active CK2 inhibitor. 3. Materials and Methods 3.1. Chemistry All indeno[1,2- em b /em ]indole derivatives 1C30 used in this study were synthesized by us. The procedures for the synthesis of indeno[1,2- em b /em ]indoles have already been described for compounds 4e [35], 4f [35], 4g [17], 4v [35], 4x [16], 4y [16], 5d [17], 5j [16], 5k [16], and 6g [16]. For the compounds 4d, 4hCj, 4pCs, 4w, 5a, 5c, 5f, 5h, 5g, and 6aCf, the chemistry is described in the Supporting Information (Files S1 and S2). Four naphtho[2,3- em b /em ]furan-4,9-dione derivatives were purchased from Life Chemicals (Woodbridge, CT, USA) and Enamine (Kyiv, Ukraine). 3.2. Computational Methods 3.2.1. Computational Study Molecular Operating Environment software package (MOE, 2016.01, Chemical Computing Group, Montreal, QC, Canada) was used to perform this study [29], running on an Intel Core, we5-6500CPU, 3.20 GHz processor. 3.2.2. Data Collection for QSAR The data for the QSAR study (IC50 ideals) was created by using the above-mentioned compounds. The compounds were divided into a training arranged with 20 compounds having IC50 ideals between 25 and 4100 nM, and a test arranged.performed the molecular modeling study, biological evaluations, and manuscript preparation. enzyme using MOE and sorted relating to their S score (energy-based scoring method implemented in MOE) to rank the best ligand in terms of the orientation and binding to the active Ampiroxicam site. The four tested compounds were selected and visual 2D and 3D inspections were carried out to exclude false positives due to assumptions and shortcomings in the docking methods and rating function [42]. The active site was analyzed to determine the proteinCligand connection to show precisely which atoms could interact. Number 3 shows the 3D and 2D relationships of the four tested compounds and it is obvious that they fit well in the ATP active site of CK2. The four docked compounds were inserted into the thin ATP binding site of CK2 (Number 3) and all of them were able to develop a C connection between the aromatic ring of the naphtho[2,3-b]furan-4,9-dione and the side-chain residues of Ile174. Compound 01893208 was also able to generate direct bonding with Asp120 and Glu123. Compound 37867960 and compound 00082235 showed direct bonding with Lys68 and via a water molecule with Glu81. Compound 01236034 had direct bonding with Val53 and via a water molecule with Glu81 as well. Emodin in the crystal structure produced a C connection with Phe113 and direct bonding with Lys68. Open in a separate window Open in a separate window Number 3 3D binding mode of the four tested compounds with the ATP binding site of CK2 with surface map (a,b) the 2D binding mode. (1) Compound 00082235; (2) Compound 01893208; (3) Compound 37867960, (4) Compound 01236034. Several studies have been performed to develop an active CK2 inhibitor using different in silico techniques [23]; however, few ligand-based drug design (LBDD) techniques were able to put forward a successful candidate [23]. Our database of indeno[1,2- em b /em ]indoles was not only used to find a list of candidates via a pharmacophore approach, but also exploited to develop a new reliable QSAR model, which we used to predict the activity of these compounds. We shown that some of the tested naphtho[2,3- em b /em ]furan-4,9-dione compounds were active using both in vitro evaluation and cellular assays. However, we were not able to correlate our expected IC50 values to the tested IC50 ideals of naphtho[2,3- em b /em ]furan-4,9-dione compounds since only four compounds were available to us. As a matter of fact, the moderate inhibitory activity of some tested naphtho[2,3- em b /em ]furan-4,9-dione derivatives was not a surprise for us, as a variance between expected and tested inhibition is expected in such QSAR studies. This was also the case in some compounds in the test set, where the r2 for the test arranged was 0.77. Regrettably, it was not possible to correlate the expected and tested values for those naphtho[2,3- em b /em ]furan-4,9-dione derivatives offered in this study, since only four of them were tested. It is important to stress that the aim of this work was to describe the inhibitory activity of 20 novel indeno[1,2- em b /em ]indoles and to show that compounds with naphtho[2,3- em b /em ]furan-4,9-dione backbone were appropriate for developing CK2 inhibitors, which was proved by compound 00082235. The future step will become optimizing this compound by synthesizing a series of compounds with different substituents on a naphtho[2,3- em b /em ]furan-4,9-dione backbone and carrying out a SAR study with the aim of finding a highly active CK2 inhibitor. 3. Materials and Methods 3.1. Chemistry All indeno[1,2- em b /em ]indole derivatives 1C30 used in this study were synthesized by us. The methods for the synthesis of indeno[1,2- em b /em ]indoles have been described for compounds 4e [35], 4f [35], 4g [17], 4v [35], 4x [16], 4y [16], 5d [17], 5j [16], 5k [16], and 6g [16]. For the compounds 4d, 4hCj, 4pCs, 4w, 5a, 5c, 5f, 5h, 5g, and 6aCf, the chemistry is usually explained in the Supporting Information (Files S1 and S2). Four naphtho[2,3- em b /em ]furan-4,9-dione derivatives were purchased from Life Chemicals (Woodbridge, CT, USA) and Enamine (Kyiv, Ukraine). 3.2. Computational Methods 3.2.1. Computational Study Molecular Operating Environment software package (MOE, 2016.01, Chemical Computing Group, Montreal, QC, Canada) was used to perform this study [29], running on an Intel Core, i5-6500CPU, 3.20 GHz processor. 3.2.2. Data Set for QSAR The data for the QSAR study.Docking Study The docking of the naphtho[2,3- em b /em ]furan-4,9-dione derivatives into the active site of the CK2 enzyme (3C13) was achieved using MOE-Dock implemented in MOE. best ligand in terms of the orientation and binding to the active site. The four tested compounds were selected and visual 2D and 3D inspections were carried out to exclude false positives due to assumptions and shortcomings in the docking methods and scoring function [42]. The active site was analyzed to determine the proteinCligand conversation to show exactly which atoms could interact. Physique 3 shows the 3D and 2D interactions of the four tested compounds and it is obvious that they fit well in the ATP active site of CK2. The four docked compounds were inserted into the thin ATP binding site of CK2 (Physique 3) and all of them were able to produce a C conversation between the aromatic ring of the naphtho[2,3-b]furan-4,9-dione and the side-chain residues of Ile174. Compound 01893208 was also able to produce direct bonding with Asp120 and Glu123. Compound 37867960 and compound 00082235 showed direct bonding with Lys68 and via a water molecule with Glu81. Compound 01236034 had direct bonding with Val53 and via a water molecule with Glu81 as well. Emodin in the crystal structure produced a C conversation with Phe113 and direct bonding with Lys68. Open in a separate window Open in a separate window Physique 3 3D binding mode of the four tested compounds with the ATP binding site of CK2 with surface map (a,b) the 2D binding mode. (1) Compound 00082235; (2) Compound 01893208; (3) Compound 37867960, (4) Compound 01236034. Several studies have been performed to develop an active CK2 inhibitor using different in silico techniques [23]; however, few ligand-based drug design (LBDD) techniques were able to put forward a successful candidate [23]. Our database of indeno[1,2- em b /em ]indoles was not only used to find a list of candidates via a pharmacophore approach, but also exploited to develop a new reliable QSAR model, which we used to predict the activity of these compounds. We exhibited that some of the tested naphtho[2,3- em b /em ]furan-4,9-dione compounds were active using both in vitro evaluation and cellular assays. Nevertheless, we were not able to correlate our predicted IC50 values to the tested IC50 values of naphtho[2,3- em b /em ]furan-4,9-dione compounds since only four compounds were available to us. As a matter of fact, the moderate inhibitory activity of some tested naphtho[2,3- em b /em ]furan-4,9-dione derivatives was not a surprise for us, as a variance between predicted and tested inhibition is expected in such QSAR studies. This was also the case in some compounds in the test set, where the r2 for the test set was 0.77. Regrettably, it was not possible to correlate the predicted and tested values for all those naphtho[2,3- em b /em ]furan-4,9-dione derivatives offered in this study, since only four of them were tested. It is important to highlight that the aim Ampiroxicam of this work was to describe the inhibitory activity of 20 novel indeno[1,2- em b /em ]indoles and to show that compounds with naphtho[2,3- em b /em ]furan-4,9-dione backbone were appropriate for developing CK2 inhibitors, which was proved by compound 00082235. The future step will be optimizing this compound by synthesizing a series of compounds with different substituents on a naphtho[2,3- em b /em ]furan-4,9-dione backbone and performing a SAR study with the aim of finding a highly active CK2 inhibitor. 3. Materials and Methods 3.1. Chemistry All indeno[1,2- em b /em ]indole derivatives 1C30 used in this study had been synthesized by us. The methods for the formation of indeno[1,2- em b /em ]indoles have been described for substances 4e [35], 4f [35], 4g [17], 4v [35], 4x [16], 4y [16], 5d [17], 5j [16], 5k [16], and 6g [16]. For the substances 4d, 4hCj, 4pCs, 4w, 5a, 5c, 5f, 5h,.