Structure-based virtual screening and ADME/T-based profiling for low molecular weight chemical starting points as p21-activated kinase 4 inhibitors

Li, Ruijuan; Su, Xiaolin; Chen, Zheng; Huang, Wanxu; Wang, Yali; Wang, Kaibo; Lin, Bin; Wang, Jian; Cheng, Maosheng

doi:10.1039/c4ra16963h

Cited by 16 publications

(5 citation statements)

References 41 publications

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“…Therefore, an ideal pharmacophore model (pharmacophore a ) was confirmed (Figures A and B), which including 1 hydrogen bond acceptor (A) mapped on the carbonyl group of the pyrrolidine, 2 hydrogen bond donors (D1 and D2) matched with hydroxamate moiety and 3 hydrophobic‐aliphatic groups (H1, H2 and H3) mapped on the phenyl group and quinolinyl group of IK682. Pharmacophore a was used as a 3D structural query for retrieving SPECS database which was prepared previously . As a result, fourteen compounds were selected based on their scaffolds and visual observations (Figure ).…”

Section: Resultsmentioning

confidence: 99%

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A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo

Zhao

Ding

et al. 2018

Cell Proliferation

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Section: Resultsmentioning

confidence: 99%

“…Pharmacophore a was used as a 3D structural query for retrieving SPECS database which was prepared previously. 41 As a result, fourteen compounds were selected based on their scaffolds and visual observations (Figure S2).…”

Section: Pharmacophore-based Virtual Screen To Identify a Potential A...mentioning

confidence: 99%

A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo

Zhao

Ding

et al. 2018

Cell Proliferation

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“… 21 The docking results and surface representation of PAK1 in complex with IPA-3, In03 and In06 were displayed in Discovery Studio 4.0 software. 22 …”

Section: Methodsmentioning

confidence: 99%

Computer-aided drug design, synthesis and identification of disulfide compounds as novel and potential allosteric PAK1 inhibitors

et al. 2018

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p21-activated kinase 1 (PAK1) is an evolutionarily conserved serine/threonine protein kinase, which has been considered as one of the key regulatory factors in signaling network of tumor cells. Therefore, inhibition of PAK1 may be a potential approach to treat many types of solid tumors. Several allosteric inhibitors of PAK1 have been identified, and the most well known one is IPA-3. But its biological activity is not satisfied, and the structure activity relationship (SAR) of PAK1 allosteric inhibitors is unclear. In this study, we designed and synthesized 13 potential allosteric inhibitors by using computer-aided drug design based on the structure of the existing PAK1 allosteric inhibitors. All the compounds were characterized by 1 H-NMR and 13 C-NMR, among which six were not reported previously. SAR was investigated by pharmacological studies and In03 and In06 showed increased PAK1 inhibition than previously reported IPA-3. These findings could guide further structure optimization of PAK1 inhibitors.

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“…The compounds with appropriate binding energy values (≤6) were selected. 19,20 Finally, sixteen compounds were chosen and purchased for in vitro bioassay testing (Table 1).…”

Section: Structure-based Virtual Screeningmentioning

confidence: 99%

Structure-based virtual screening and ADME/T-based prediction analysis for the discovery of novel antifungal CYP51 inhibitors

et al. 2018

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With the increasing incidence of pathogenic fungi and drug-resistant fungi in clinic, it has become very important to develop the novel rate-limiting enzyme 14α-demethylase (CYP51) as an antifungal inhibitor. In this study, a method involving structure-based virtual screening was employed. First, a publicly available database was obtained from the Dow Chemical Company, and the database was screened by the designed pharmacophore model of CYP51 inhibitors. Then, the pharmacophore search hits were docked into the CYP51 crystal structure. Finally, sixteen compounds were selected for antifungal inhibition assay, and most of the compounds showed a certain degree of antifungal activity. In particular, compounds, , and exhibited significant antifungal and anti-drug resistance activities by blocking the synthesis of ergosterol. The molecular docking and ADME/T properties of the compounds ,, and were further predicted, and the results indicated that they can form hydrophobic and coordination interactions with the active sites of CYP51. At the same time, compounds and showed promising drug-like properties. This study reveals that the compounds can be further optimized and developed as lead compounds.

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Structure-based virtual screening and ADME/T-based profiling for low molecular weight chemical starting points as p21-activated kinase 4 inhibitors

Abstract: Novel PAK4 inhibitors were discovered using structure-based virtual screening approach for further chemical modification.

Cited by 16 publications

References 41 publications

A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo

A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5‐Fluorouracil by reversing Notch and epithelial‐mesenchymal transition in vitro and in vivo

Computer-aided drug design, synthesis and identification of disulfide compounds as novel and potential allosteric PAK1 inhibitors

Structure-based virtual screening and ADME/T-based prediction analysis for the discovery of novel antifungal CYP51 inhibitors

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