Probing Diversity in Binding Affinities of Polymorphs of an Anticancer Agent against Human γ‑Enolase: A Quantum Crystallographic Perspective

Functions of a biological system are governed by a molecular recognition process which may turn baffling in the case of polymorphic drugs with distinct modes of action. To examine the electronic factors that direct the interactions at the active site of a target leading to the diverse binding affinities, here, we study three polymorphic forms of an anticancer agent. We perform experimental charge density analyses to highlight the differences and similarities of their topological properties. At the molecular level, we compare their geometries, orbital energies, binding energies, and topological properties of electron densities to monitor the changes that polymorphic ligands may undergo upon complexation with human γ-enolase. Further, we investigate the preferential binding mechanism of the ligands based on both electrostatic complementarity analysis and the study of enzyme–ligand interactions in the molecular dynamics simulated complex structure via noncovalent interactions analysis. Thus, we probe the root of the diversity in binding affinities of the polymorphs using quantum crystallographic approaches. The findings from these experimental and computational studies are expected to assist the drug development process.