Exploring the binding mechanism of positive allosteric modulators in human metabotropic glutamate receptor 2 using molecular dynamics simulations.

Positive allosteric modulators (PAMs) of human metabotropic glutamate receptor 2 (hmGlu2) are well-known in the treatment of psychiatric disorders for their higher selectivity and lower tolerance risk. A variety of PAMs have been reported over the last decade and two compounds were in Phase II clinical trials for schizophrenia and anxiety. These trials were discontinued on account of the unsatisfactory therapeutic efficacy, but PAMs were explored as novel treatments for addiction and epilepsy. Thus, it is still important to explore novel hmGlu2 PAMs in the near future. Nowadays, the challenges in optimizing drug potency and improving scaffold diversity for PAMs are the noncomprehensive character analyses of multiple scaffolds; the exploration of the binding modes of PAMs in the allosteric binding site have been proposed to reduce this difficulty. However, there has been no comprehensive research about the binding profiles of PAMs in the hmGlu2 receptor. To address this issue, this work explores the binding characters of eight PAMs representing five chemical series by multiple computational methods. As a result, the shared binding modes of the eight studied PAMs interacting with 15 residues in the allosteric binding site were defined. In addition, the reduced hydrophobicity with low electronegativity of R1, increased hydrophobicity with low negative electron density of R2 and the electronegativity of the linker were identified as indicators that regulate the affinity of PAMs. This finding agrees well with the physicochemical properties of reported multiple series PAMs. This comprehensive work sheds additional light on the binding mechanism and physicochemical regularity underlining PAMs affinity and could be further utilized as a structural and energetic blueprint for discovering and assessing novel PAMs for hmGlu2.

Profiling the structural determinants of aminoketone derivatives as hNET and hDAT reuptake inhibitors by field-based QSAR based on molecular docking.

BACKGROUND: Bupropion, one of the dual norepinephrine and dopamine reuptake inhibitors (NDRIs), is an aminoketone derivative performed effect in improving cognitive function for depression. However, its therapeutic effect is unsatisfactory due to poor clinical response, and there are only few derivatives in pre-clinical settings. OBJECTIVE: This work attempted to elucidate the essential structural features for the activity and designed a series of novel derivatives with good inhibitive ability, pharmacokinetic and medicinal chemistry properties. METHODS: The field-based QSAR of aminoketone derivatives of two targets were established based on docking poses, and the essential structural properties for designing novel compounds were supplied by comparing contour maps. RESULTS: The selected two models performed good predictability and reliability with R2 of 0.8479 and 0.8040 for training set, Q2 of 0.7352 and 0.6266 for test set respectively, and the designed 29 novel derivatives performed no less than the highest active compound with good ADME/T pharmacokinetic properties and medicinal chemistry friendliness. CONCLUSIONS: Bulky groups in R1, bulky groups with weak hydrophobicity in R3, and potent hydrophobic substituted group with electronegative in R2 from contour maps provided important insights for assessing and designing 29 novel NDRIs, which were considered as candidates for cognitive dysfunction with depression or other related neurodegenerative disorders.

An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary.

A practical method for the removal of a versatile acidic amide auxiliary has been developed. Facile alcoholysis of the amide in the presence of KOAc is enabled by an epoxide, which mechanistically resembles the removal of the Myers' auxiliary. The protocol has been applied to the removal of a variety of amide substrates and their C-H functionalization products with high efficiency and low cost, representing a step forward toward the development of a versatile directing group for C-H activation.

Catalytic asymmetric 1,6-Michael addition of arylthiols to 3-methyl-4-nitro-5-alkenyl-isoxazoles with bifunctional catalysts.

An enantioselective 1,6-Michael addition reaction of arylthiols to a wide range of 3-methyl-4-nitro-5-alkenyl-isoxazoles catalyzed by readily available Takemoto's thiourea catalyst has been developed. This reaction provides a useful catalytic method for the synthesis of optically active chiral sulfur compounds bearing a 4-nitroisoxazol-5-yl moiety in high to excellent yields (up to 97%) and high enantioselectivities (up to 91% ee). Significantly, the potential utilities of the protocol had been further demonstrated by gram-scale reaction and the versatile conversions of some resulting products into other functionalized and useful compounds.

Highly enantioselective construction of spiro[4H-pyran-3,3'-oxindoles] through a domino Knoevenagel/Michael/cyclization sequence catalyzed by cupreine.

The first enantioselective organocatalytic two- and three-component reactions via a domino Knoevenagel/Michael/cyclization sequence with cupreine as catalyst have been developed. A wide range of optically active spiro[4H-pyran-3,3'-oxindoles] were obtained in excellent yields (up to 99%) with good to excellent enantioselectivities (up to 97%) from simple and readily available starting materials under mild reaction conditions. These heterocyclic spirooxindoles will provide promising candidates for chemical biology and drug discovery.