Virtual screening is the computational mirror image of high-throughput screening and refers to the in silico evaluation of the biological activity of different molecular entities. Various virtual screening strategies and workflows have been adopted to enhance the process of identification of potential hits. Structure-based scoring relies solely on the interactions between the ligand and the target protein. Conversely, pharmacophore-based scoring relies on the shape complementation of each ligand candidate to a three-dimensional reference ligand. Herewith, we report a systematic integrated hybrid approach, along with the use of well-defined physicochemical and biological filters, to enhance high-ranking hit structures complementing the binding site architecture while also mimicking the three-dimensional features of known active ligands.
With a lack of experimental data on the South African HIV protease enzyme (C-SA HIV PR), very limited research has been conducted to design inhibitors against this enzyme variant. In this paper, a focused integrated structure- and pharmacophore-based virtual screening protocol is introduced to identify potential leads to assist toward designing potent inhibitors against the C-SA PR variant. This rapid and systematic approach can potentially be implemented for the design and discovery of inhibitors against a wide range of biological targets.