Diffusion of the small, very polar, drug piracetam through a lipid bilayer: an MD simulation study

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Ribeiro, RP (Author) Other; Coimbra, JTS (Author) Other; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Theoretical Chemistry Accounts

Vol. 136

ISSN: 1432-881X

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 12 Citations

Other information

Authenticus ID: P-00M-KQE

DOI: 10.1007/s00214-017-2073-3

Abstract (EN): One of the major goals to improve drug discovery is to understand the molecular properties that influence oral bioavailability. Molecular dynamics-based methods have been used to understand passive diffusion with atomic detail and to predict diffusivities and permeabilities. In this paper, we explore the structural and dynamic behavior of piracetam, a nootropic drug, using umbrella sampling, as it crosses a 1,2-dioleoyl-sn-glycero-3-phosphocholine bilayer model. This is accompanied with a potential of mean force profile, showing the partition equilibrium within the bilayer. We discuss important molecular properties and their influence to the permeation of this important drug. Piracetam changes its solution-dominant conformation, modifying its polar surface area and forming an internal hydrogen bond, to facilitate penetration into the hydrophobic core. Rotation and orientation patterns, as piracetam diffuses across the membrane, were also analyzed, and we found out that in bulk water and at the membrane center piracetam shows no specific orientation as it rotates quickly and freely, whereas near the phospholipids' polar head groups its polar atoms are much more oriented and the rotation is slowed down by more than one order of magnitude. Altogether, the study provides a very detailed view of the events mediating the permeation of this small and very polar drug.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10