In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity.

José A H M Bittencourt,Luciane B Silva,Renata C V S Bittencourt,Pedro S Lacerda,Rai C Silva,Cleison C Lobato,Juliana P Zuliani,Franco H A Leite,Rosivaldo S Borges,Cleydson B R Santos,Joaquín M C Rosa,Moysés F A Neto

doi:10.3390/molecules24081476

Abstract

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.

Highlights

The organism is constantly subject to stimuli and aggressions that can cause infections and tissue damage
Studieswere employed to predict the affinity binding of ibuprofen derivatives Molecular docking studies into a cyclooxygenase isoform
COX-2 binding site.thePredicting binding geometries and Molecular docking studies were to predict affinity binding of ibuprofen into a cyclooxygenase isoform or COX-2 binding site

Summary

Introduction

The organism is constantly subject to stimuli and aggressions that can cause infections and tissue damage. As a defense mechanism, the biological system developed an adaptive response that seeks to circumvent a tissue aggression, called inflammation. Inflammation is a complex event that involves a perfect and coordinated cascade of cellular and molecular events that aims to remove the harmful stimulus and restore damaged tissue. Acute inflammation is a short duration process (hours to months), and involves mediators such as prostanoids and nitric oxide (NO) substances that provoke the initial classic signs of the inflammatory process (pain, heat, flushing and edema, with or without loss of function in the tissue of the affected organ) [6,7]. Acute inflammation may be terminated by resolution of all events characteristic of the inflammatory reaction and return of the injured tissue to normality or its replacement by connective tissue [8,9]

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