Malaria is due to the Plasmodium protozoon. The parasite infects human red blood cells, where it digests hemoglobin, in the end releasing free heme (Fe-protoporphyrin IX, FePPIX) in the cytosol. There, FePPIX could produce reactive oxygen species which are toxic to the parasite. As a defense mechanism, the protozoon deactivates FePPIX by promoting its biocrystallization into hemozoin, a triclinic harmless solid. It is largely accepted that 4-aminoquinoline (AQ) drugs, and in particular the low-cost compound chloroquine (CQ), interfere with this detoxification process , but no unequivocal evidences on their mechanism of action still exist [2,3]. Moreover, emerging parasite resistance made CQ ineffective in the last decades. In this context, understanding the mechanism of action of chloroquine is a key point to develop novel cheap CQ-based compounds, exploitable in large-scale health campaigns, able to thwart the parasite resistance. In our very recent work , evidences of the existence of a direct Fe – N coordinative bond between CQ and heme in solution have been obtained. DFT calculations highlighted that charge-assisted hydrogen bonds (CAHBs) among the hydrocarbon chain of CQ and the propionate groups of heme play a crucial role in the molecular recognition, particularly in the presence of lipidic micelles. In this contribution we report on a high-resolution low-temperature single crystal X-ray diffraction study on the chloroquine diphosphate dihydrate salt. CQ crystallizes as P21/c, with dihydrogenphosphate ions (H2PO4–) forming infinite chains parallel to the monoclinic axis. Doubly protonated CQ molecules, CQH22+, and H2PO4– are connected through strong N-H•••O CAHBs. A π-π stacking interaction could be also set up between the quinoline rings, which lie parallel to the (a,c) plane to occupy as much as possible the free space between phosphate chains. From the molecular recognition viewpoint, π-π stacking in the CQ crystal could be taken as a model for the π-π CQ:heme interaction in solution, described in the literature as a possible way of interaction between the drug and its substrate, while negatively charged the phosphate ions behave as propionate groups in heme. The study of the CQ self-recognition energies through the analysis of the primary charge density confirm the hypothesis that the coulombic interactions between CQ and the phosphate are the real dominant ones, while the stacking between the quinoline moieties has just an ancillary role. These evidences further confirm that the protonated tertiary amine of CQ is an essential component of the drug pharmacophore.  A. F. G. Slater, W. J. Swiggard, B. R. Orton, W. D. Flitter, D. E. Goldberg. A. Cerami, G. B. Henderson Proc. Natl. Acad. Sci. USA 1991, 88, 325-329.  M. S. Walckzak, K. Lawniczak-Jablonska, A. Wolska, A. Sienkiewicz, L. Suarez, A. J. Kosar, D. S. Bohle J. Phys. Chem. B, 2011, 115, 1145-1150.  A. C. De Dios, R. Tycko, L. M. B. Ursos, P. D. Roepe J. Phys. Chem. A, 2003, 107, 5821-5825.  G. Macetti, S. Rizzato, F. Beghi, L. Silvestrini, L. Lo Presti Physica Scripta 2016, 91, 023001, 1-13.
Experimental and theoretical study of the mechanism of action of the antimalarial drug chloroquine / G. Macetti, S. Rizzato, L. Loconte, C. Gatti, L. Lo Presti. ((Intervento presentato al 4. convegno Meeting of the Italian and Spanish crystallographic associations (MISCA) tenutosi a Puerto de la Cruz nel 2016.
|Titolo:||Experimental and theoretical study of the mechanism of action of the antimalarial drug chloroquine|
MACETTI, GIOVANNI (Primo)
RIZZATO, SILVIA (Secondo)
LO PRESTI, LEONARDO (Corresponding)
|Data di pubblicazione:||giu-2016|
|Parole Chiave:||Antimalarial; chloroquine; self-recognition; DFT-calculations|
|Settore Scientifico Disciplinare:||Settore CHIM/02 - Chimica Fisica|
|Citazione:||Experimental and theoretical study of the mechanism of action of the antimalarial drug chloroquine / G. Macetti, S. Rizzato, L. Loconte, C. Gatti, L. Lo Presti. ((Intervento presentato al 4. convegno Meeting of the Italian and Spanish crystallographic associations (MISCA) tenutosi a Puerto de la Cruz nel 2016.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|