Exploring the Conformational Dynamics and Key Amino Acids in the CD26-Caveolin-1 Interaction and Potential Therapeutic Interventions

Abstract

Abstract The study focused on the interaction between CD26 and caveolin-1, and employed zDOCK to identify two binding conformations, con1 and con4. Molecular dynamics simulations and alanine scanning were performed to analyze the contribution of key amino acids in the CD26 and caveolin-1 interaction. The 100ns simulation trajectories revealed that con1 exhibited smaller fluctuations and displayed more stable thermodynamic characteristics compared to con4. In con1, specific interactions were observed, including CD26's GLU237 forming a hydrogen bond with F chain's TYR151, CD26's TYR24 engaging in a π-π interaction with F chain's PHE160, CD26's TYR248 forming π-π interactions with G and H chains' PHE160, CD26's ARG147 forming a π-π interaction with I chain's TYR148, CD26's GLY99 participating in a cation-π interaction with J chain's TYR151, and CD26's PHE98 forming a hydrogen bond with J chain's TYR151. In con4, CD26's ARG253 formed a hydrogen bond with J chain's THR95, CD26's LYS250 interacted with the J chain's PHE99 through hydrogen bonding and π-π interactions, and CD26's TYR248 engaged in a π-π interaction with J chain's TRP98. Based on the information about the key amino acids involved in the CD26 and caveolin-1 interaction, a high-throughput virtual screening of small molecule compounds was conducted using the Traditional Chinese Medicine Library and the Anti-diabetic Compound Library. Crocin, Poliumoside, and Canagliflozin were identified as compounds with high docking scores and favorable binding modes to CD26 and caveolin-1. These compounds primarily interacted with CD26 and caveolin-1 through hydrogen bonding and hydrophobic interactions. Interestingly, Canagliflozin was also found to interact through π-π interactions with CD26 and caveolin-1 binding sites. This study represents the first elucidation of the preferred conformations and key amino acids involved in the CD26 and caveolin-1 interaction. The identification of these key amino acids contributes to a better understanding of the structure-function relationship in protein binding and provides important insights for further research and drug design. Additionally, the virtual screening identified potential small molecule compounds (Crocin, Poliumoside, and Canagliflozin) that have the potential to inhibit tumor growth and metastasis, alleviate inflammatory responses, and regulate metabolic processes by targeting the CD26 and caveolin-1 interaction. However, further in vitro and in vivo experiments are required to validate these findings before the research can progress into clinical translation. In conclusion, a comprehensive understanding of the CD26 and caveolin-1 interaction contributes to the elucidation of the pathological mechanisms underlying relevant diseases and provides new targets and strategies for disease treatment and intervention.