Fanhong Wu

Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations.

An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.

Superacid-catalyzed tandem Meyer–Schuster rearrangement/intramolecular hydroamination of o-anilinopropargyl alcohols for the synthesis of 2,3-dihydro-4(1H)-quinolones

ABSTRACT A TfOH-catalyzed synthesis of 2,3-dihydro-4(1H)-quinolones from o-anilinopropargyl alcohols was developed. Studies of N-protecting groups and substituents in phenyl rings showed that diverse groups could be applied. By controlling the catalyst loading, o-anilinopropargyl alcohols underwent the expected transformation smoothly to produce N-protected or N-deprotected 2,3-dihydro-4 (1H)-quinolones in good yields. This transformation probably involved a tandem Meyer–Schuster rearrangement/intramolecular hydroamination reaction process. GRAPHICAL ABSTRACT

Discovery of (E)-1-amino-4-phenylbut-3-en-2-ol derivatives as novel neuraminidase inhibitors

Neuraminidase has been considered as an important target for designing agents against influenza viruses. In a discovery of anti-influenza agents with epigoitrin as the initial lead compound, a series of 1-amino-2-alkanols were synthesized and biologically evaluated. The in vitro evaluation indicated that (E)-1-amino-4-phenylbut-3-en-2-ol (C1) had better inhibitory activities than 2-amino-1-arylethan-1-ol derivatives. To our surprise, sulfonation of C1 with 4-methoxybenzenesulfonyl chloride afforded more active inhibitor II with up to 6.4 μM IC50 value against neuraminidase. Furthermore, docking of inhibitor II into the active site of NA found that the H atoms in both NH2 and OH groups of inhibitor II were the key factors for potency. Molecular docking research did not explained very well the observed structure-activity relationship (SAR) from amino acid residue level, but also aided the discovery of (E)-1-amino-4-phenylbut-3-en-2-ol derivatives as novel and potent NA inhibitors.

Identification of 2,4-diarylaminopyrimidine analogues as ALK inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

Anaplastic lymphoma kinase (ALK) is a particularly promising target for the development of small molecule anti-cancer drugs. In the present study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 60 ALK inhibitors to build three-dimensional quantitative structure–activity relationship models. Both the ligand-based resultants of CoMFA (r2 0.970, q2 0.660) and CoMSIA (r2 0.979, q2 0.623) models exhibited good predictability. The resulting contour maps illustrated the regions where interactive fields may affect the activity. Molecular docking was then performed to explore the interactions between these inhibitors and the ALK-4DCE protein. A few key residues (His32, Gly31, Gly169, Asp170, Val35, Ala100, Pro160, Lys50, and Leu30) at the binding site of 4DCE were identified. Molecular dynamics simulation further verified the reliability. The information acquired in this work not only provides a better appreciation of interactions between these molecules and the ALK receptor but could also be applied to design more effective ALK inhibitors.Graphical abstract