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Front. Pharmacol. | doi: 10.3389/fphar.2018.00395

Aromatic rings commonly used in medicinal chemistry: Force fields comparison and interactions with water towards the design of new chemical entities

 Marcelo D. Polêto1, Victor H. Rusu2,  Bruno I. Grisci3,  Marcio Dorn3, Roberto D. Lins4 and  Hugo Verli1*
  • 1Centro de Biotecnologia, Federal University of Rio Grande do Sul (UFRGS), Brazil
  • 2Swiss National Supercomputing Centre, Switzerland
  • 3Instituto de Informática, Federal University of Rio Grande do Sul (UFRGS), Brazil
  • 4Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Brazil

The identification of lead compounds usually includes a step of chemical diversity generation.
Its rationale may be supported by both qualitative (SAR) and quantitative (QSAR) approaches,
offering models of the putative ligand-receptor interactions. In both scenarios, our understanding
of which interactions functional groups can perform is mostly based on their chemical nature (such
as electronegativity, volume, melting point, lipophilicity etc.) instead of their dynamics in aqueous,
biological solutions (solvent accessibility, lifetime of hydrogen bonds, solvent structure etc.). As a
consequence, it is challenging to predict from 2D structures which functional groups will be able
to perform interactions with the target receptor, at which intensity and relative abundance in the
biological environment, all of which will contribute to ligand potency and intrinsic activity. With this
in mind, the aim of this work is to assess properties of aromatic rings, commonly used for drug
design, in aqueous solution through molecular dynamics simulations in order to characterize their
chemical features and infer their impact in complexation dynamics. For this, common aromatic and
heteroaromatic rings were selected and received new atomic charge set based on the direction
and module of the dipole moment from MP2/6-31G* calculations, while other topological terms
were taken from GROMOS53A6 force field. Afterwards, liquid physicochemical properties were
simulated for a calibration set composed by nearly 40 molecules and compared to their respective
experimental data, in order to validate each topology. Based on the reliance of the employed
strategy, we expanded the dataset to more than 100 aromatic rings. Properties in aqueous
solution such as solvent accessible surface area, H-bonds availability, H-bonds residence time and water structure around heteroatoms were calculated for each ring, creating a database of potential interactions, shedding light on features of drugs in biological solutions, on the structural basis for bioisosterism and on the enthalpic/entropic costs for ligand-receptor complexation dynamics.

Keywords: drug design, aromatic rings, interactions, GROMOS, functional groups

Received: 09 Nov 2017; Accepted: 05 Apr 2018.

Edited by:

Adriano D. Andricopulo, São Carlos Institute of Physics, University of São Paulo, Brazil

Reviewed by:

Antonio Monari, Université de Lorraine, France
Gustavo Trossini, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Brazil  

Copyright: © 2018 Polêto, Rusu, Grisci, Dorn, Lins and Verli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Hugo Verli, Federal University of Rio Grande do Sul (UFRGS), Centro de Biotecnologia, Porto Alegre, Rio Grande do Sul, Brazil,