Evaluation and Optimisation

The Human Immunodeficiency Virus (HIV), has led to the emergence of Acquired Immunodeficiency Syndrome. The Reverse Transcriptase (RT) enzyme, which is involved in viral replication, was used as a target, to design novel molecules, mainly Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). NNRTIs bind away from the catalytic site of RT and exert a conformational change to the structure of the enzyme inhibiting its conversion from viral RNA to DNA. Protein Data Bank crystallographic depositions describing the bound co-ordinates of different NNRTIs bound to the RT enzyme, namely 3HVT, 2ZD1, 4NCG, 3DRP and 3DOL, were modelled in SYBYL®X-1.2. The apo form of the enzyme was obtained and the Ligand Binding Pocket was mapped. Phase 1 of the study consisted of modifying lead molecules to create seeds differing in magnitude and growing site loci. These in turn were planted in the RT key-site using the GROW module of LigBuilder® V2. Molecular growth was carried out according to the pre-established growing sites and novel structures with different pharmacophores were generated.