Theoretical study of the interaction between Zidovudine (and novel derivatives) and the human serum albumin

TOSSOLINI, I.; ´GÓMEX, M.C.; QUEVEDO, M.A.

Santiago de Chile - Chile

Congreso; 2da. Reunion de la International Society for Computational Biology; 2012

International Society for Computational Biology

Human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS), a disease that affects the immune system and produces its inability to cope with infections and other pathological processes. Until now, no cure has been found due to the fact that the standard methodology for developing vaccines cannot be used. Given this situation, AIDS is treated with antiretroviral cocktails, in which Zidovudine (AZT) is included. AZT was the first drug approved for AIDS treatment by the Food and Drug Administration (FDA) in 1986. Despite its effectiveness, AZT has significant adverse effects, many of them associated to low plasma protein binding, including the human serum albumin (HSA). Hence, obtaining AZT prodrugs, with higher affinity for HSA, is a key strategy to increase the effectiveness of the drug. The main strategy commonly used is the chemical modification by making use of functional groups of diverse nature, at the 5’-OH position of the molecule, thus producing the AZT derivatives (Fig. 1). HSA is present in the human body in its pure form (HSAP), predominantly in the extravascular compartment, and complexed with fatty acids (HSAFA) in the intravascular compartment. The binding of fatty acids to HSA causes a differential affinity of the drugs administered for therapeutic purposes, which can lead to the accumulation of them in a particular compartment in response to its higher affinity for HSAP or HSAFA. Owing to the fact that both species exhibit different biodistribution, the computational studies aimed at obtaining a detailed description of the topology of the site in HSA (HSAP and HSAFA) where AZT binds (Sudlow Site 1) (Fig. 2). This was done in order to determine the molecular aspects that lead to different affinities of the AZT and its derivatives [1], for both species of HSA, establishing a qualitative (structural) and quantitative (energetic) relationship between the chemical structure and the fraction of the bound drug. It would contribute to the development of anti-HIV drugs. In order to design AZT derivatives with increased affinity for HSAP and HSAFA, molecular modeling methodologies, docking and molecular dynamics were applied, based on the crystallographic structures of HSAP (PDB 1BM0) and HSAFA complexed with myristate (Myr) (PDB 3B9L).