Evaluation and Optimisation. Of in silico designed HIV Reverse Transcriptase Modulators

      Аннотация: 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.

Ключевые слова: evaluation, Optimisation, Management, Option