Lead optimisation: Improving the affinity of the antiretrovirals Nelfinavir and Amprenavir for HIV-1 protease

• Type: Article in International Scientific Journal
• Date: 2006

Authors

Fernandes, PA (Author) FCUP; Araujo, MLAC (Author) Other; Barbosa, AJM (Author) Other; Alves, CN (Author) Other; Ferreira, ZQ (Author) Other; R N Gonzalez (Author) Other; Lima, CFRAC (Author) Other; Loureiro, SIE (Author) Other; Magalhaes, JMT (Author) Other; Maia, FC (Author) Other; Moura, SA (Author) Other; Peredo, EMM (Author) Other; Perez, MAS (Author) Other; Rodrigues, TAQ (Author) Other; Pessoa, AM (Author) Other; da Silva, CAM (Author) Other; da Silva, JPA (Author) Other; Ramos, MJ (Author) FCUP

Journal

Title: Letters in Drug Design and Discovery

Vol. 3

Pages: 383-389

ISSN: 1570-1808

Publisher: Bentham Science

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 1 Citation

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-004-J8Y

DOI: 10.2174/157018006777805576

Abstract (EN): Nelfinavir (Viracept, Pfizer), and Amprenavir (Ageneraze(R), GlaxoSmithKline) are potent bioavailable inhibitors of the enzyme Protease (PR) of the Human Immunodeficiency Virus-1 (HIV-1), which have been developed by consistent structure-based drug design projects, and have been approved worldwide for the treatment of HIV infected patients. They act as competitive inhibitors, and tightly bind the active site of PR with high shape and electrostatic potential complementarily. However, the virus has shown the ability of fixating mutations which decrease the affinity of the antiretrovirals for the binding pocket of PR, although at the cost of decreasing (but to a minor extent) the affinity for the substrate. The consequent appearance of drug resistance compromised the long term efficacy of the drug. In this work we have extended such structure based drug design effort with computational methodologies, by performing very small substitutions in the inhibitors, directed at interacting with the most conserved amino acids. It is not possible to mutate the latter, at the cost of making the enzyme catalytically inactive. We show with a set of examples that significant increases in affinity can still be achieved without changing the overall structure, molecular mass and hydrophobicity of the inhibitors, thus preserving their very favourable ADME properties.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 7