Research Projects

Obesity remains a growing global health burden, driven by the imbalance between excessive caloric intake and insufficient energy expenditure. Existing Monotherapies that target either pancreatic lipase (PL) to reduce fat absorption or adipose tissue (AT) to enhance thermogenesis have demonstrated only modest and often transient efficacy. PL inhibition limits dietary fat absorption at the gastrointestinal level; they are commonly associated with hepatic and gastrointestinal side effects. Moreover, long-term inhibition may lead to compensatory metabolic adaptations, reducing their sustained efficacy. On the other hand, agents that target AT to promote lipolysis, browning, or non-shivering thermogenesis aim to enhance energy expenditure. However, their impact remains suboptimal when caloric intake is not simultaneously controlled. These agents also face additional hurdles, including poor tissue selectivity, low systemic bioavailability, and limited metabolic stability. To address these limitations of these approaches, this project proposes a dual-target pharmacological strategy that integrates both PL inhibition and AT activation within a single small molecule. The central hypothesis is that a rationally designed small molecule can be structurally optimised to concurrently suppress energy intake and stimulate energy expenditure, thereby achieving synergistic and sustained anti-obesity effects. Building on our patented lead compound, BITS-NPRG-243, a reported PL inhibitor, we aim to engineer dual-functional analogues. Using structure-guided design and computational modelling, we will strategically introduce modifications to enable dual-target engagement. Particular emphasis will be placed on optimizing lipophilicity, improving metabolic stability, and utilizing ester-based prodrug strategies to facilitate peripheral bioavailability and AT tissue targeting. The specific scientific objectives are as follows: 1.To perform molecular modeling and computational screening of the patented in-house lead PL inhibitor (BITS-NPRG-243) to identify key structural and physicochemical features necessary for dual-target optimization. 2.To design, synthesize, and characterize a rationally optimized series of analogues based on computational insights 3.To conduct PL enzyme-based assays and adipocyte cell-based studies to evaluate the efficacy of the optimized analogues 4.To perform in vivo toxicological, anti-obesity (high-fat-diet model), and pharmacokinetic studies of the new lead analogue. Methodology: • Synthesis of designed analogues • In vitro lipase inhibition assays to determine enzyme activity. • 3T3-L1 cell-based studies with expression profiling of specific markers. •Acute and sub-chronic oral administration in HFD-induced obese animals to evaluate weight gain, lipid profiles, glucose tolerance, and adipose tissue histology. • Gene and protein expression studies to assess molecular pathways involved. •Pharmacokinetics and toxicokinetic assessment If successful, this study will establish a new model for dual-target anti-obesity agents, combining input and output energy regulation within a single molecule. The findings are expected to contribute fundamentally to our understanding of structure–activity relationships in multifunctional drug design. It simultaneously provides translational value for metabolic disease therapy. This work has the potential to expand the therapeutic store with next-generation, mechanism-based agents for obesity and associated metabolic disorders.