9GCX

Crystal structure of bovine Cytochrome bc1 in complex with inhibitor F8

This is a non-PDB format compatible entry.

Summary for 9GCX

• Entry DOI: 10.2210/pdb9gcx/pdb
• Descriptor: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 10, (1R)-2-{[(R)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(DODECANOYLOXY)METHYL]ETHYL (9Z)-OCTADEC-9-ENOATE, ... (20 entities in total)
• Functional Keywords: mitochondrial electron transport chain, antimalarial, electron transport
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 11
• Total formula weight: 300086.15

Authors

Pinthong, N.,Hong, W.,ONeill, P.W.,Antonyuk, S.V. (deposition date: 2024-08-03, release date: 2025-01-22)

Primary citation

Ge, S.,Jian, R.,Xuan, Q.,Zhu, Y.,Ren, X.,Li, W.,Chen, X.,Huang, R.K.,Lee, C.S.,Leung, S.C.,Basilico, N.,Parapini, S.,Taramelli, D.,Pinthong, N.,Antonyuk, S.V.,O'Neill, P.M.,Sheng, Z.,Hong, W.D.
Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties.
Eur.J.Med.Chem., 284:117228-117228, 2024

PubMed Abstract: Aryl quinolone derivatives can target the cytochrome bc complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce π-π stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20 μM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.

PubMed: 39752821
DOI: 10.1016/j.ejmech.2024.117228

Experimental method

X-RAY DIFFRACTION (3.522 Å)