For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.

Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC 50 ranging from 1 to 100 nM and 11 compounds with IC 50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC 50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.

No abstract

Aim: To study the conformational changes of Aβ 42 and discover novel inhibitors of both Aβ 42 aggregation and β-secretase (BACE1). Methods: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aβ 42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aβ 42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening. Results: The initial α-helical conformation of Aβ 42 , which was unstable in aqueous solution, turned into a β-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aβ 42 mainly comprising β-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aβ 42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aβ 42 aggregation and BACE1, with IC 50 values of 36.95 μmol/L and 22.70 μmol/L, respectively. Conclusion: A helical to β-sheet conformational change in Aβ 42 occurred in a 1.8 microsecond MD simulation. The resulting β-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aβ 42 aggregation. Five compounds were identified as inhibitors of Aβ 42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aβ 42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.

No abstract

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure-activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

No abstract

Glucan phosphatases are members of a functionally diverse family of dual-specificity phosphatase (DSP) enzymes. The plant glucan phosphatase Starch Excess4 (SEX4) binds and dephosphorylates glucans, contributing to processive starch degradation in the chloroplast at night. Little is known about the complex kinetics of SEX4 when acting on its complex physiologically relevant glucan substrate. Therefore, we explored the kinetics of SEX4 against both insoluble starch and soluble amylopectin glucan substrates. SEX4 displays robust activity and a unique sigmoidal kinetic response to amylopectin, characterized by a Hill coefficient of 2.77 ± 0.63, a signature feature of cooperativity. We investigated the basis for this positive kinetic cooperativity and determined that the SEX4 carbohydrate-binding module (CBM) dramatically influences the binding cooperativity and substrate transformation rates. These findings provide insights into a previously unknown but important regulatory role for SEX4 in reversible starch phosphorylation and further advances our understanding of atypical kinetic mechanisms.