In silico enzyme engineering of aldehyde dehydrogenase for eco-friendly ibuprofen synthesis

Abstract

Ibuprofen is the most widely utilized nonsteroidal anti-inflammatory drug (NSAID) for managing pain and inflammation globally. However, traditional chemical synthesis methods for producing ibuprofen are not environmentally friendly, as they involve hazardous reagents, high energy consumption, and significant chemical waste, along with toxic effluents. The rising global demand for ibuprofen necessitates the exploration of alternative biocatalytic approaches. This study focuses on developing an enzyme through in silico driven rational enzyme discovery and engineering to convert ibuprofen aldehyde into ibuprofen. The current study demonstrates a unique biocatalytic synthesis of ibuprofen from ibuprofen aldehyde using aldehyde dehydrogenase enzyme (bcPADH), providing a greener alternative by reducing the number of reaction steps from six to four. Furthermore, the solvent tolerance of the enzyme, which is crucial for its practical application in industrial processes has been enhanced, using advanced molecular dynamics simulations and experimental validations. Among the engineered variants, bcPADH01 demonstrated the highest stability and conversion efficiency (>80%) in 30% DMSO. Our findings demonstrate that in silico strategies are fundamental for rational enzyme design which is required for advancing biocatalytic innovation.