Published June 30, 2021 | Version v1
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QSAR analysis and molecular docking study of pyrrolo- and pyridoquinolinecarboxamides with diuretic activity

Creators

  • 1. National University of Pharmacy
  • 2. V. N. Karazin Kharkiv National University
  • 3. Danylo Halytsky Lviv National Medical University

Description

The aim. The aim of the study was to reveal QSAR and ascertain the possible mechanism of action via docking study in the row of tricyclic quinoline derivatives with diuretic activity.

Materials and methods. Pyrrolo- and pyridoquinolinecarboxamides with proven diuretic activity were involved in the study. Molecular descriptors were calculated using HyperChem and GRAGON software, and QSAR models were built using BuildQSAR software. For receptor-oriented flexible docking, the Autodock 4.2 software package was used.

Results. Multivariate linear QSAR models were built on two datasets of quinolinecarboxamides: Vol = a∙X1 + b∙X2 + c∙X3 + d, where Vol – volume of the daily produced urine in rats, Xi – molecular descriptor. QSAR analysis showed that the diuretic activity is determined by the geometric and spatial structure of molecules, logP, the energy values, RDF- and 3D-MoRSE-descriptors. Based upon internal and external validation of the models, the most informative two-parameter linear QSAR model 3а was proposed. Docking data showed the high affinity of two lead compounds to the carbonic anhydrase II.

Conclusions. QSAR analysis of tricyclic quinoline derivatives revealed that the diuretic activity increases with the increase of value of logP, refractivity, and dipole moment and with the decrease of volume, surface area, and polarization of the molecules. Increase of values of such energy descriptors as bonds energy, core-core interaction, and energy of the highest occupied molecular orbital results in higher diuresis; decrease in hydration energy leads to higher diuretic activity. Based upon molecular docking calculation, the mechanism of diuretic action is proposed to be carbonic anhydrase inhibition.

QSAR models and docking data are useful for in-depth study of diuretic activity of tricyclic quinolines and could be a theoretical basis for de novo-design of new diuretics

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