3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model

Abstract

Urease enzyme (EC 3.5.1.5) has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship) advance studies were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q2) value of 0.597 and correlation coefficients (r2) of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q2 and r2 of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r2pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches

“…Finally, the lowest energy conformer was selected from all the resulting structural conformations. The partial charges were calculated using different methods including GH, GM, and MMFF94 charges [ 31 , 32 ]. Because the alignment of molecules is believed to be the most crucial and important requirement for a 3D-QSAR model’s robustness and predictability, the alignments were performed based on common substructures of the template molecule and all the other compounds present in the dataset.…”

Enzyme Inhibitory Kinetics and Molecular Docking Studies of Halo‐Substituted Mixed Ester/Amide‐Based Derivatives as Jack Bean Urease Inhibitors

“…It is statistically calculated that nearly half of the world's population suffer due to Helicobacter pylori [ 15 – 18 ]. Some other bacteria, mainly Proteus , Klebsiella , Pseudomonas , and Staphylococcus species, lead to kidney stones, often called infectious stones, such as struvite (magnesium ammonium phosphate) [NH 4 MgPO 4 .6H 2 O)] and carbonate apatite [Ca 10 (PO 4 ) 6 CO 3 ] [ 19 , 20 ]. The congenital problems associated with a well-known urease inhibitor hydroxamic acids limit its clinical utility.…”

5-[(3-Fluorophenyl)(2-hydroxy-6-oxocyclohex-1-en-1-yl)methyl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

“…The barbituric acid skeleton represents an important structural motif that is embodied in a number of pharmaceutical agents with activities including anti-osteoporosis [1][2][3], anticonvulsant [4,5], urease inhibition [6,7], sedation, anesthesia [8,9], hypnosis [10], anti-oxidant [11], radio-sensitization, tyrosinase or alpha-glucosidase inhibition [12,13], anti-bacterial [14], anti-fungal [14], anti-cancer [14], and anxiolytic effects [3]. Many of these representatives are in clinical use as hypnotic and anti-inflammatory drugs; for example, sodium pentothal, phenobarbital, veronal, seconal, and bucolome [8,9].…”