In silico design of small peptides antagonist against leptin receptor for the treatment of obesity and its associated immune-mediated diseases.

Excess adiposity in obese inhibits negatively impacts immune function and host defence. Obesity is characterized by a state of low-grade, chronic inflammation in addition to disturbed levels of circulating nutrients and metabolic hormones. The impact of metabolic abnormalities on obesity-related co-morbidities has undergone intense scrutiny over the past decades. Thus, treatment of obesity and its associated immune-mediated diseases is challenging due to impaired function of leptin system. These disorders are managed through antibiotics and by cytokines replacement. However, the effectiveness of cytokines coupled to the complexity of the cytokine network leads to severe side-effects, which can still occur after careful preclinical evaluation. In addition, synthetic immunotherapeutics carry a degree of risk, time-consuming and expensive. Hence, the complexity of existing therapy and adverse effects emphasizes the need for an alternative approach for the management of immune dysfunction associated with obesity. Computer-aided small molecule antibody technology has been successful in the design of novel biologicals for the diagnosis of diseases and therapeutic interventions. In this study, the crystal structure of leptin receptor (LEPR) complex with monoclonal antibody (9F8 Fab) was explored to predict Ag-Ab interactions using bioinformatics tools. The LEPR of complementarity-determining region (CDR) loops were mutated with published positive control residues of Ser, Thr, Tyr, Trp, and Phe to design a set of 678 peptides which were evaluated through Ag-peptide docking, binding free-energies, and interaction energies. Thus, hypothesized novel peptides can be explored as clinically applicable antagonists for the treatment of obesity and associated immune-mediated diseases.