Unraveling Interleukin-1β inhibition: Computational insights into anti-inflammatory compound selection for inflammatory disorders.

The multifaceted impact of IL-1β has been proposed to have a central role in a spectrum of immunological responses spanning physiological reactions to aggressive inflammatory reactions and autoimmune disorders. Once IL-1β binds to its cognate receptor it initiates IL-1R1/TLR4 signaling cascade, leading to transcriptional modifications that sustain the inflammatory response. Extensive structural and functional investigations on IL-1β have yielded various inhibitors aimed at disrupting the formation of ligand receptor complex. Unfortunately, most have proven unsuccessful in clinical trials. Therefore, directing efforts towards IL-1β/IL-1R1 presents a unique opportunity to formulate an alternative therapy for the treatment of inflammatory disorders. In view of this, the present study aimed to identify small molecules obstructing protein-protein interactions (PPIs) to impede heterocomplex formation. In this context, a search query was formulated by integrating a ligand-based pharmacophore mapping alongside a multi-stage molecular docking to assess the potential of the predicted hits in terms of binding modes within the targeted cavity of the IL-1β and the associated binding affinities. Thus, via a stepwise screening process starting from an initial pool of 40,000 compounds, 8 potential hits were identified for detailed atomic studies employing molecular dynamic simulation encompassing a total time frame of 0.9 μs. The investigation in dynamic behavior was followed by the estimation of free energies using molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The stability matrices revealed that the chosen virtual hits possess a notable potential to hinder the complex formation between IL-1β/IL-1RI. The average backbone deviations recorded for the conformational ensembles of the ligand free IL-1β/IL-1RI exhibited significant dynamics, featuring the average value of 0.35 nm. Conversely, the identified hits particularly, inhouse-2603 and inhouse-1325 demonstrated a high degree of stability with mean values of 0.32 ± 0.05, 0.31 ± 0.03, respectively. The residue-wise fluctuations were maximum for Compound-1303, with the mean value of 0.31 nm and minimal for Compound-2691 with the mean value 0.21 nm. The MMPBSA revealed the highest binding energy of -89.50 ± 10.63, and -81.32 ± 14.9 kcal/mol, for the IL-1β/IL-1RI complex with compound-2603, and Compound-1325 respectively. The principal component analysis (PCA) in conjunction with free energy landscape (FEL) further shed light on the conformational space in terms of energetic stability. Considering the essential role of IL-1β in mediating several inflammatory cascades, it is proposed that the identified PPI inhibitors since demonstrated stable behavior and promising attributes in regard to inhibitory potential as outlined by mechanistic exploration, may serve as new chemotypes for the future exploration aimed at mitigation inflammatory disorders.