Molecular modelling of chloride recognition and transmembrane transport by hydrazone-based synthetic receptors

• Autor(a) principal: Soares, Márcio Miguel da Silva
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/32829
• topic: Channelopathies; Cystic fibrosis; Synthetic receptors; Anion transmembrane transport; Molecular dynamics simulations; Molecular modelling; Anion recognition

The transport of ionic species across biological membranes, often mediated by embedded proteins, is vital for numerous biological processes. The slightest malfunction on this complex cellular cascade is associated with several channelopathies, such as cystic fibrosis, characterised by a deficient chloride transport through the cystic fibrosis transmembrane conductance regulator (CFTR) protein channel. Current treatments mainly focus on attenuating the diseases’ symptoms, instigating the need for alternative therapies, such as channel replacement therapies (CRTs), based on the development of synthetic receptors. However, the design of these small drug-like molecules is still not fully understood, as it depends on a perfect balance between the transporter’s binding affinity and lipophilicity. This work aimed to obtain theoretical insights into the anion chloride recognition and transport properties of thiourea-based acylhydrazones. As such, a family of thioureas functionalized with acylhydrazones and related functional groups undergone thorough experimental and computational studies. The receptors’ affinity for chloride was evaluated by DFT calculations while the interaction and the passive diffusion of receptors and their chloride complexes were investigated through molecular dynamics (MD) simulations based on classical force fields. The experimental chloride transport studies suggest that the additional binding motif has a detrimental effect of the transport ability of the thiourea-based receptors, as additional interactions between the secondary binding unit and the membrane phospholipids inhibit the anion transport. This hypothesis is strongly supported by the orientation of the transporters in the membrane and respective interactions, as observed MD simulations.