Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

Abstract

A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and pi-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC(50) < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC(50) > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition.

3D QSAR Pharmacophore Modeling, in Silico Screening, and Density Functional Theory (DFT) Approaches for Identification of Human Chymase Inhibitors

“…reported their discovery that electrostatic interactions accounted for the majority of the rate acceleration in the mechanism of RNA transphosphorylation in solutions catalyzed by the hairpin ribozyme [63]. Daga and Doerksen have stated the binding mode and the role of stereoelectronic properties in binding of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activities [64]. Recently, the electrostatic funnel illuminated from three-dimensional mapping of the electrostatic potential was reported by Dehez et al ., driving the diphosphate nucleotide rapidly toward the bottom of the internal cavity of membrane-protein mitochondrial ADP/ATP carrier by forming a privileged passageway [65].…”

Bifunctional Cinchona Alkaloid Thiourea Catalyzed Highly Efficient, Enantioselective Aza‐Henry Reaction of Cyclic Trifluoromethyl Ketimines: Synthesis of Anti‐HIV Drug DPC 083

“…Dihydroquinazolinones, as an important class of heterocyclic compounds are characterized by their broad spectrum of intriguing biological properties, such as antiviral4 and antiobesity activities,5 and their use in the treatment of cardiovascular diseases6 and pain 7. Notably, among these compounds, drug candidates DPC 083 and DPC 961, bearing a chiral trifluoromethyl moiety, are potent HIV‐1 nonnucleoside reverse transcriptase inhibitors (Scheme ) 1.…”

Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition

“…As the predictability of a QSAR model is best judged by the external validation using a test set compounds, the data set was divided into training and test sets. Training set included compounds labeled as 1,2,4,6,12,14,15,19,22,24,25,27,31,32, and 34. We adopted multiple validation strategies like LOO cross-validation and external validation.…”