Tuning Potency of Bioactive Molecules via Polymorphic Modifications: A Case Study

Abstract

Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained as one of the critical issues in drug development processes. While improving physicochemical properties of bioactive molecules has been a prime focus of the pharmaceutical chemists, not much efforts have been put toward the improvement of their potency via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and discover eights polymorphs in three out of the five cases. We perform systematic crystallization experiments and detailed crystal structure analysis of the eight polymorphs and two compounds, estimate both their energetic and thermal stabilities, and compare their solid state properties. We also compare in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability, of three polymorphs of one of the cases. Further, we study the extent of inhibition imposed by those eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and also the extent of their binding to the isozyme γ-enolase. Furthermore, we perform MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with γ-enolase. Our experimental and MD simulation analyses in general emphasize the importance of polymorphism in improving the biological potency of individual molecules.

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

“…Although some of us reported the details of the MD simulations in an earlier study, here we summarize the steps. Initially, the polymorphic ligands 1a , 1b , and 1c were docked into the binding site of γ-enolase (PDB ID: 1TE6) using AutoDock Vina implemented in the UCSF Chimera.…”

“…Further details of the crystallizations are reported elsewhere. 8 High-Resolution X-ray Diffraction Data Collection Strategy. Excellent quality single crystals of the polymorphic forms (Figure S1) were selected for high-resolution X-ray diffraction data collection at a low temperature using a Bruker APEX3 diffractometer equipped with D8 Venture IμS microfocus dual sources and PHOTON II CPAD detector.…”

“…38 Given their biological importance, we had undertaken systematic crystallization experiments in an earlier study to discover polymorphs. 8 Here, we report high-resolution X-ray diffraction based charge density analysis on three polymorphic forms (1a, 1b and 1c) of (Z)-5-(4-(dimethylamino) benzylidene)-2-(piperidin-1-yl) thiazol-4(5H)-one (1, Scheme 1), a known anticancer agent. 8,38 We highlight the differences and similarities of the bond topologies among the trimorphs and correlate their electronic features with their binding affinities to the target enzyme, human γ-enolase.…”

“…Numerous reports suggest that the molecular conformation of ligands in the crystalline environment correlates well with that of the target-bound state. − Therefore, the binding pattern of the polymorphic drugs with different conformations at the active site of the same target is likely to vary and lead to a different binding affinity. In this context, very recently, some of us have studied eight polymorphic forms of three derivatives of an anticancer agent to emphasize the role of polymorphism in improving the biological potency of individual molecules . The study also sheds light on establishing structure–activity–property relationships in bioactive molecules.…”

“…In human breast cancer cells MCF7 and MDA454, 5-arylidenethiazolidinones were found to be effective antiproliferative agents, and γ-enolase was identified as a potential target for some of those derivatives . Given their biological importance, we had undertaken systematic crystallization experiments in an earlier study to discover polymorphs …”