On the Potency of Polymorphic Bioactive Molecules: A Quantum Crystallographic Perspective

Parthapratim Munshi

Multifunctional Molecular Materials Laboratory,

Department of Chemistry, School of Natural Sciences,

Shiv Nadar Institution of Eminence Deemed to be University,

Delhi NCR, 201314, UP, India

e-mail: parthapratim.munshi@snu.edu.in

Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained one of the critical issues in the drug development process. While improving the physicochemical properties of bioactive molecules has been a prime focus of pharmaceutical chemists, not much effort has been put into improving their potency via polymorphic modifications.

Here, we considered five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and eight newly discovered polymorphs in three of the five cases. We performed systematic crystallization experiments, detailed analysis of crystal structures, estimated their energetics and thermal stabilities, and compared their solid-state properties. We also compared in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability of three polymorphic forms of one case. Further, we studied the extent of inhibition imposed by the eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and the extent of their binding to the isozyme g-enolase. Furthermore, we performed MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with g-enolase. Our experimental and MD simulation analyses emphasized the importance of polymorphism in improving the biological potency of individual molecules. We believe many more such a systematic study would allow pharmaceutical industries screening potent drugs efficiently and avoid any disaster as evidenced earlier.

Further, we studied three of these polymorphs to examine the electronic factors that direct the interactions at the active site of a target leading to the diverse binding affinities. For this, we performed experimental charge density analyses to highlight the differences and similarities of their topological properties. We compared the geometries, orbital energies, binding energies, and topological properties of electron densities at the molecular level to monitor the changes that polymorphic ligands may undergo upon complexation with human g-enolase. Further, we investigated the ligands' preferential binding mechanism based on the electrostatic complementarity analysis and the study of enzyme-ligand interactions in the MD simulated complex structure via NCI analysis. Thus, we probed 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 alleviate the drug development process.

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