Discovery of New 4‐Alkoxyquinazoline‐Based Derivatives as Potent VEGFR2 Inhibitors

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty‐one 4‐alkoxyquinazoline‐based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC₅₀ values of 2.89 nm (for VEGFR2) and 0.25  μ m (for MCF‐7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site.     

Structure‐guided Discovery of a Novel Non‐peptide Inhibitor of Dengue Virus NS2B–NS3 Protease

Dengue fever is a fast emerging epidemic‐prone viral disease caused by dengue virus serotypes 1‐4. NS2B–NS3 protease of dengue virus is a validated target to develop antiviral agents. A major limitation in developing dengue virus protease inhibitors has been the lack of or poor cellular activity. In this work, we extracted and refined a pharmacophore model based on X‐ray crystal structure and predicted binding patterns, followed by a three‐dimensional flexible database filtration. These output molecules were screened according to a docking‐based protocol, leading to the discovery of a compound with novel scaffold and good cell‐based bioactivity that has potential to be further optimized. The discovery of this novel scaffold by combination of in silico methods suggests that structure‐guided drug discovery can lead to the development of potent dengue virus protease inhibitors.     

Identification of Novel HCV RNA‐dependent RNA polymerase Inhibitors Using Pharmacophore‐Guided Virtual Screening

We performed pharmacophore‐guided virtual screening experiments using FlexX‐Pharm to identify novel inhibitors of hepatitis C virus RNA‐dependent RNA polymerase. Pharmacophore model generated from our previous analysis of the binding modes as well as structure‐based three‐dimensional quantitative structure–activity relationship studies of aryl diketoacid analogues was used. In pharmacophore‐guided virtual screening study, among 37 447 compounds in LeadQuest chemical library, 40 compounds were selected as novel candidates of hepatitis C virus RNA‐dependent RNA polymerase inhibitors, and their biological activities were evaluated. Especially, T29 was chosen for further development.     

Synthesis of Novel Pyrimidin‐4‐One Bearing Piperazine Ring‐Based Amides as Glycogen Synthase Kinase‐3β Inhibitors with Antidepressant Activity

Novel pyrimidin‐4‐one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase‐3β (GSK‐3β) inhibitors. Among all the synthesized compounds, compound 5 (3‐methyl‐6‐phenyl‐2‐(piperazin‐1‐yl)‐3,4‐dihydropyrimidin‐4‐one) exhibited the most potent inhibitory activity against GSK‐3β with IC₅₀ value of 74 nm . The molecular docking studies were performed to elucidate the binding modes of the compounds with the target, and a crucial interaction involving hydrogen bond formation with Val‐135 to the active site of GSK‐3β was observed. Furthermore, the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity, and compound 5 showing highest inhibition of GSK‐3β was also found to significantly reduce the duration of immobility at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of inhibitors of GSK‐3β with antidepressant activity.     

Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking

Lysine‐specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore‐based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC₅₀ values in a range of 2.41–101 μm . Furthermore, compound XZ 09 exhibited less inhibition against the homologous monoamine oxidase A (MAO‐A) and B (MAO‐B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers.     

Discovery of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl)acetonitriles as phosphodiesterase 4 inhibitors with anti‐neuroinflammation potential based on three‐dimensional quantitative structure–activity relationship study

Phosphodiesterase 4 (PDE4) inhibitors with potential activities for CNS disorders provide a new therapeutic strategy for depression. To discover PDE4 inhibitors with anti‐neuroinflammation activities, reliable three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on our previous reported catecholic PDE4 inhibitors was built with a statistically significant cross‐validated coefficient (q²), conventional coefficient (r²), and good predictive capabilities based on the molecular docking results, using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods. Based on the analysis of CoMFA and CoMSIA contour maps, a series of 2‐(3,4‐dialkoxyphenyl)‐2‐(substituted pyridazin‐3‐yl) acetonitriles 16a–i was designed and synthesized. Among these compounds, compound 16a exhibited good inhibitory activities toward PDE4B1 and PDE4D7 with mid‐nanomolar IC₅₀ values and potential anti‐neuroinflammation activity in BV‐2 cells. Docking simulation of compound 16a in the PDE4 catalytic domain activity pocket revealed that compound 16a maybe assumed a “V‐shaped” conformation, extending the side chain to S‐pocket.     

Structure‐Based Design of a Novel Class of Potent Inhibitors of InhA,the Enoyl Acyl Carrier Protein Reductase from Mycobacterium Tuberculosis: A Computer Modelling Approach

The NADH‐dependent Enoyl‐ACP reductase (InhA) of Mycobacterium tuberculosis has been shown to be the primary target of the frontline drug isoniazid (INH). However, INH must be first activated by katG gene, mutations in which have mediated resistance to INH. Recently, direct inhibitors of InhA have been reported. Using a structure‐based approach, we have identified a tripeptide inhibitor with the sequence WYW, which is 100 times more potent than the existing inhibitors. It is therefore, a potential lead compound for the development of new anti‐TB drugs.