Abstract:
Human Immunodeficiency Virus (HIV) protease is retro pepsin, essential in the life cycle of
the HIV virus causing Acquired Immuno Deficiency Syndrome (AIDS). HIV protease plays
an essential role in the maturation of infectious virions. HIV-1 protease inhibitors cause
inhibition of this activity however, the use of these HIV protease inhibitors have been
reported to cause hyperlipidemia, lipodystrophy, liver toxicities and hyperinsulinemia. The
outcome of hyperinsulinemia is Type 2 Diabetes. Various studies revealed the increase risk of
Diabetes Mellitus in HIV protease therapy patients. One of the major reasons of this outcome
is the overlap in substrates/inhibitors profile of HIV protease and various glucose
transporters. GLUT4 has been known as the major glucose transporter in cells therefore,
selectivity of HIV-protease inhibitors against GLUT-4 is of prime importance while
designing new drug candidates for HIV treatment. In this project various structure based in
silico strategies have been utilized to design novel, potent and selective inhibitors of HIV
proteases. Our results demonstrates the importance of Leu B23, Asp A25, Val A32, Asp
B25, Ile A50, Asp B25, Gly A27 and Asp A29 for the selective interaction of HIV-protease inhibitors . Final and selective pharmacophoric pattern of HIV-protease inhibitors consist of
one hydrogen bond donor, one hydrogen bond acceptor, one hydrophobic and one aromatic
feature. The present study could pave the way towards design of highly selective, potent
inhibitors of HIV-protease with minimum risk of diabetes.
