A comparative study of AutoDock and PMF scoring performances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors

Abstract

4-Alkylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, 4-arylmethylidenehydrazino-1H-pyrazolo[3,4-d]pyrimidines, and 2-substituted 7H-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidines as potential xanthine oxidase inhibitors were docked into the active site of the bovine milk xanthine dehydrogenase using two scoring functions involved in AutoDock 3.05 and the CAChe 6.1.10. The correlation coefficiency obtained between the AutoDock binding energy and IC(50) of the inhibitors was better than that obtained by the CAChe-PMF docking score. Many ligands exhibited one to four hydrogen bonds within the active site, where the detected hydrogen bonds by CAChe was identified quantitatively in the docked conformation by using MOPAC 2002. These ligands were docked into a long, narrow channel of the enzyme leading to the molybdopterin active moiety, with hydrogen bonding and electrostatic interaction between the planar aromatic moiety of the ligand and the enzyme. Furthermore, SAR among inhibitors was investigated, which revealed that the oxo group of pyrazolopyrimidine analogs is essential for its activity and the tricyclic derivatives are shown to be more potent than bicyclic ones. The mode of interaction of the docked inhibitors was described in details.

Binding interaction between rice glutelin and amylose: Hydrophobic interaction and conformational changes

“…After 100 docking runs, energy minimization was conducted to get the best structure, which also belonged to the best cluster. According to Ali et al [31], the overall docking energy of ligand molecule in its binding site is expressed as follows: Estimated G binding = intermol energy (van der Waals + hydrogen bond + electrostatic interactions + desolvation energy) + torsional energy.…”

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

“…Substituents on the amino group at position 4 of compound 51 resulted in very potent inhibitors of XO with hydrazone 55 being the most active in the series . SAR studies conducted on hydrazones 56 showed that the planar orientation of the pyrazolopyrimidine moiety inside the narrow channel of the enzyme active site allowed van der Waals interactions with Phe914 and Phe1009, in addition to numerous hydrogen bonds between the inhibitor and the active site of the enzyme …”

Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of Imidazolone Fused Pyrazolo[1,5‐a]pyrimidine Derivatives

“…Pyrazolo[1,5‐a]pyrimidines are also bioisosteres for triazolothienopyrimidines, imidazoquinazolines, pyrimidoquinazolines, and imidazoquinolinones, all of which have shown reported to exhibit good anticancer activity. Furthermore, pyrazolo[1,5‐a]pyrimidines have been reported to show tuberculostatic , neuroleptic , CNS depressant , antihypertensive , antileishmanial , and antimicrobial activities .…”