The Paal–Knorr synthesis of furan, pyrrole and thiophene rings is one of the most important methods of generating these very important heterocycles, but the mechanism of this reaction is not well understood. Though several mechanistic paths are suggested, the exact energy requirements of this reaction, the structural features of transition states associated with the cyclization step, have not been established, especially for furan and thiophene synthesis. In this work, we explore the mechanism of the Paal–Knorr method and establish the energy requirements, using quantum chemical methods. The Paal–Knorr reaction to give furans is endergonic by 3.7 kcal mol⁻¹ whereas the same reaction is exergonic for pyrrole and thiophene generation by 16.4 and 15.9 kcal mol⁻¹, using G2MP2 method. The cyclization step is associated with high energy barrier, however, explicit water participation reduces the barrier significantly. For example, under the neutral condition two water mediated pathways – (i) monoenol and (ii) hemiketal, are possible on the reaction leading to furan. The cyclization step in these two pathways require 28.9 and 27.1 kcal mol⁻¹, respectively. The ring formation step becomes highly favorable in the presence of H₃O⁺ with a barrier of only 11.5 kcal mol⁻¹ (solvent phase) from the monoenol to dihydrofuran derivative and 5.5 kcal mol⁻¹ (solvent phase) from hemiketal to dihydroxy dihydrofuran derivative. Similarly, a water mediated pathway involving the intermediacy of hemialcohols has been found to be energetically preferred mechanism for pyrrole and thiophene also.

Glycogen synthase kinase-3 is a constitutively acting, multifunctional serine threonine kinase, the role of which has been implicated in several physiological pathways and has emerged as a promising target for the treatment of type-II diabetes and Alzheimer’s disease. In order to provide a detailed understanding of the origin of selectivity determinants of ATP competitive inhibitors, molecular dynamics simulations in combination with MM-PBSA binding energy calculations were performed using crystal structures of GSK-3β and CDK-2 in complex with 12 ATP competitive inhibitors. Analysis of energy contributions indicate that electrostatic interaction energy dictates the selectivity of ATP competitive inhibitors against CDK-2. Key interactions as well as residues that potentially make a major contribution to the binding free energy were identified at the ATP binding site. This analysis stresses the need for the inhibitors to interact with Lys85, Thr138, and Arg141 in the binding site of GSK-3β to show selectivity. The residue-wise energy decomposition analysis further suggested the additional role of Gln185 in determining the selectivity of maleimides. The results obtained in this study can be utilized to design new selective GSK-3 ATP competitive inhibitors.

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively acting multifunctional serine/threonine kinase, a role of which has been marked in several physiological pathways, making it a potential target for the treatment of many diseases, including Type-II diabetes and Alzheimer’s. Design of GSK-3β selective inhibitor was the key challenge which led to the use of rational approaches like structure based methods (molecular docking), and ligand based methods (QSAR, pharmacophore mapping) studies. These methods provide insights into the enzyme–ligand interactions and structure activity relationship of different sets of compounds for the design of promising GSK-3 inhibitors. Molecular dynamic simulation studies have additionally been performed to address key issues like the unique requirement of prime phosphorylation of its substrate at P+4 by GSK-3β. An allosteric site has also been reported, where the binding of the peptide leads to the stabilization of the activation loop, resulting in the enhancement of the catalysis of enzymes. These studies are becoming useful in the design of therapeutically active discriminatory GSK-3 inhibitors. In this article, we present a review of recent efforts and future opportunities for the design of selective GSK-3β inhibitors.