Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing

TLDR

Hydrogen bonding and hydrophobic interactions stabilize ligands in protein environments, yet how these interactions guide drug‑lead recognition and efficacy remains poorly understood. The study analyzes hydrophobic interactions, hydrogen bonding, and binding affinity at the c‑Src/c‑Abl kinase interface with 4‑amino‑substituted pyrazolo‑pyrimidine compounds to elucidate drug‑target recognition. In‑silico docking using Discovery Studio (LigandFit, CDOCKER, ZDOCK), LigPlot interaction mapping, and 3D‑QSAR/MFA analyses were employed to quantify weak interactions at the c‑Src/c‑Abl kinase binding pockets. The results show that a multi‑targeted small molecule binds weakly but its affinity can be enhanced by adding conformationally favored functional groups, and that optimized hydrogen bonding and hydrophobic interactions stabilize ligands and improve binding affinity and drug efficacy.

Abstract

Background Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. Methodology In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. Conclusions The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy.