Research Projects

This project aims to engineer Short-chain Dehydrogenases/Reductases (SDRs)—a diverse class of NAD(P)H-dependent oxidoreductases—using a structure-guided approach to expand their catalytic repertoire. Short-chain dehydrogenases/reductases (SDRs) represent one of the largest enzyme families, catalyzing NAD(P)H-dependent redox reactions across diverse substrates. Despite their utility in stereoselective reductions of ketones, imines, anthrols, and related compounds, their natural catalytic scope and selectivity are limited, hindering their broader application in synthetic chemistry. This project proposes a structure-guided engineering approach to expand the catalytic versatility of three key SDR subclasses—imine reductases (IREDs), keto reductases (KREDs), and anthrol reductases (ARs)—for the stereodivergent synthesis of complex, pharmaceutically relevant chiral scaffolds. This will enable us to a) To develop engineered IREDs for the asymmetric synthesis of chiral benzoxazine and dibenzothiazepine scaffolds, overcoming limitations in enantiomeric excess and substrate scope; b) To create KREDs capable of reducing sterically hindered ketones to form challenging chiral propargyl alcohols, valuable intermediates in drug synthesis. c) To generate stereoinverted ARs for the chemoenzymatic synthesis of (S)-dihydroanthracenones, enabling access to rare (+)-enantiomers of bisanthraquinone natural products such as rugulosin and 2,2’-epi-cytoskyrin A. By integrating site-directed mutagenesis, site-saturation mutagenesis, random mutagenesis (error-prone PCR), and molecular modeling, this project aims to identify and modify key active-site residues to enhance enzyme activity, broaden substrate tolerance, and invert stereoselectivity. The engineered enzymes will be evaluated for chemo-, regio-, and enantioselectivity, and structure–activity relationship (SAR) models will be built to guide further optimization. This work will establish a biocatalytic platform for the green, scalable, and stereodivergent synthesis of valuable N-heterocycles, propargyl alcohols, and complex natural product intermediates. It contributes directly to the advancement of enzyme engineering, sustainable manufacturing, and synthetic biocatalysis, with wide implications for drug discovery and fine chemical production. By expanding the functional space of SDRs, this project is expected to make significant contributions to green chemistry, sustainable manufacturing, and the broader biocatalysis landscape in India. The project is also in alignment with the newly launched BioE3 policy which aims to foster the use of enzymes in the production of valuable chemicals.