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Abstract Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials.
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This content will become publicly available on January 21, 2027
Physical–chemical approach to identify local structural determinants of molecular mechanisms: Case study of antimalarial drug pyronaridine and crystal-growth inhibition
Understanding how specific molecular substructures control chemical behavior is central to rational molecular design and the development of new materials. However, most current predictive models offer limited mechanistic resolution at the fragmental level. We present a conceptually novel use of fragment-based structure–activity reasoning, based on systematically perturbing a parent molecule, to quantify fragment-level contributions to both a specific mechanistic action and a broader functional outcome. As a case study, we investigated local structural contributions to pyronaridine (PY), a clinically used antimalarial drug with a mechanistically distinctive mode of inhibition of hematin crystal growth via step-bunching. Chemically plausible PY molecular analogs have been computationally generated by selectively removing or substituting functional groups hypothesized to influence either step-bunching mechanisms or whole-parasite blood-stage activity. For each analog, we predicted the probability of four different crystal-growth inhibition mechanisms using a centroid-based similarity model based on a small dataset of experimentally verified crystal-growth inhibitors. The blood-stage antimalarial activity has also been estimated using the MAIP platform. A systematic comparison of molecular analogs revealed that step-bunching mechanisms depend primarily on two protonated pyrrolidines, with chlorobenzene as a strong secondary contributor. In contrast, antimalarial activity is more distributed, relying on coordinated interactions between aromatic–heteroatom scaffolds and an amine linker. The obtained results demonstrate that our approach can disentangle position-specific and cooperative fragmental effects, offering mechanistically interpretable guidance for the design of mechanism-optimized inhibitors. The framework might be broadly applicable across chemical and materials domains where linking local structure to specific mechanisms is essential.
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- Award ID(s):
- 2019745
- PAR ID:
- 10687604
- Publisher / Repository:
- AIP Publishing
- Date Published:
- Journal Name:
- The Journal of Chemical Physics
- Volume:
- 164
- Issue:
- 3
- ISSN:
- 0021-9606
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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