Wei-Li Dong

Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 μM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives.

The design of novel inhibitors for treating cancer by targeting CDC25B through disruption of CDC25B-CDK2/Cyclin A interaction using computational approaches

Cell division cycle 25B is a key cell cycle regulator and widely considered as potent clinical drug target for cancers. This research focused on identifying potential compounds in theory which are able to disrupt transient interactions between CDC25B and its CDK2/Cyclin A substrate. By using the method of ZDOCK and RDOCK, the most optimized 3D structure of CDK2/Cyclin A in complex with CDC25B was constructed and validated using two methods: 1) the superimposition of proteins; 2) analysis of the hydrogen bond distances of Arg 488(N1)-Asp 206(OD1), Arg 492(NE)-Asp 206(OD1), Arg 492(N1)-Asp 206(OD2) and Tyr 497(NE)-Asp 210(OD1). A series of new compounds was gained through searching the fragment database derived from ZINC based on the known inhibitor-compound 7 by the means of “replace fragment” technique. The compounds acquired via meeting the requirements of the absorption, distribution, metabolism, and excretion (ADME) predictions. Finally, 12 compounds with better binding affinity were identified. The comp#1, as a representative, was selected to be synthesized and assayed for their CDC25B inhibitory activities. The comp#1 exhibited mild inhibitory activities against human CDC25B with IC50 values at about 39.02 μM. Molecular Dynamic (MD) simulation revealed that the new inhibitor-comp#1 had favorable conformations for binding to CDC25B and disturbing the interactions between CDC25B and CDK2/Cyclin A.

Design Novel Inhibitors for Treating Cancer by Targeting Cdc25B Catalytic Domain with De Novo Design

The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.

Design and synthesis of imidazolidine-2,4-dione derivatives as selective inhibitors by targeting protein tyrosine phosphatase-1B over T-cell protein tyrosine phosphatase.

Owing to its special role as a negative regulator in both insulin and leptin signaling, protein tyrosine phosphatase‐1B (PTP1B) has drawn considerable attention as a target for treating type 2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a series of compounds were discovered to inhibit PTP1B based on imidazolidine‐2,4‐dione by means of ‘core hopping’. A selective PTP1B inhibitor (comp#h) was identified, and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes.

Ethyl 4-[(4-chloro-phen-oxy)meth-yl]-2-(4-nitro-phen-yl)-1,3-thia-zole-5-carboxyl-ate.

The title compound, C19H15ClN2O5S, contains two molecules (A and B) in the asymmetric unit. In molecule A, the dihedral angles between the thiazole ring and the pendant chlorobenzene and nitrobenzene rings are 72.14 (15) and 3.03 (15)°, respectively. The corresponding angles for molecule B are 45.56 (16) and 1.51 (14)°, respectively. In the crystal, both molecules form inversion dimers linked by pairs of weak C—H⋯O interactions.

1-(4-Methoxy-phen-yl)imidazolidine-2,4-dione.

In the title compound, C10H10N2O3, the dihedral angle between the benzene and imidazolidine rings is 6.0 (4)°, consistent with an essentially planar molecule. In the crystal, intermolecular N—H⋯O hydrogen bonding between centrosymmetrically related molecules leads to loosely associated dimeric aggregates. These are connected into a three-dimensional network by C—H⋯O interactions, as well as π–π interactions [centroid–centroid distances = 3.705 (3) and 3.622 (3) Å] between the imidazolidine and benzene rings.

The derivatives of oseltamivir design passing through the important cleft of neuraminidase against influenza virus by de novo design

Owing to its unique function to release the progeny virus particles from the surface of an infected cell, neuraminidase has drawn special attention for developing new drugs to treat influenza viruses. The 150-cavity that is adjacent to the active pocket of the group-1 neuraminidase (N1) renders the conformational change from ‘open’ form to ‘closed’ form when enzyme is binding with a ligand. Consequently, it would be a better strategy to design multi-binding-site inhibitors including X and R groups with proper shapes, sizes and electronic charges fitting into the active site. The NCI and ZINC fragment databases were screened for finding the optimal fragments with de novo design technique. By doing so, 24 derivatives of oseltamivir were obtained by linking the fragments at two different sites of the scaffold of oseltamivir. Molecular docking and dynamics showed that these compounds not only adopt more favourable conformation but also have stronger binding interaction with receptor. Most importantly, all compounds skilfully pass through the cleft (formed by Glu119 and Arg156) and fit into 150-cavity. Therefore, the selected 24 derivatives may become promising candidates for treating influenza virus; in addition, the findings reported here may at least provide useful insights and stimulate new strategy in this area.

3-Hy-droxy-methyl-1-(4-meth-oxy-phen-yl)imidazolidine-2,4-dione.

In the title molecule, C11H12N2O4, the dihedral angle between the benzene ring and imidazolidine ring is 7.1 (5)°. In the crystal structure, the hydroxy groups are involved in the formation of intermolecular O—H⋯O hydrogen bonds, which link the molecules related by translation into C(2) chains along the b axis.

3-Bromo-1-(3-chloro-pyridin-2-yl)-N-(4-eth-oxy-phen-yl)-1H-pyrazole-5-carbox-amide.

In the title compound, C17H14BrClN4O2, the pyrazole ring is almost coplanar with the benzene ring [dihedral angle = 0.5 (2)°], whereas the pyrazole ring is close to perpendicular to the 3-chloropyridine ring [dihedral angle = 73.7 (2)°]. An intramolecular C—H⋯O hydrogen bond occurs. The dominant interaction in the crystal packing is an N—H⋯N hydrogen bond, which generates a chain along the c axis. Weak intermolecular C—H⋯O and C—H⋯N contacts are also observed