A structure-based drug discovery (SBDD) strategy was followed by using the quinoxaline derivative (ZINC 08382282, previously identified as a glucansucrase inhibitor by other authors) as lead molecule to perform a search for similar compounds with FTrees Fragment Space. The Fragment Space Package used was KnowledgeSpace_2.0_20160614 and all the procedure was run on EVOspace-search workflow for KNIME (KNIME Analytics Platform 2.11.3). The node Search FTrees Fragment Space rendered the best results when it was configurated as follow: Number of results _300, Target similarity _0.9, Target diversity _1. The screening of all similars was done by docking them into the active site of the glucansucrase GTF 180-substrate complex pdb code: 3HZ3, using the LeadIT node. The binding modes of compounds were visualized and evaluated with the node Interactive SeeSAR Viewer. Two compounds showed the higher binding affinity, ligand efficiency and torsion. One of this is a very fresh or new compound, not previously synthesized, at least up to where I know. Currently I’m about to get some hundred milligrams of it in collaboration with a research group from Spain. So, probably by the next month I will be trying its inhibitory effects in vitro. If all goes well new variants of it will be synthesized to further potentiate its inhibitory effects. On the other hand, I also did the screening of a library of 248 furanic compounds. The furanic compounds rendered several candidates which could be further optimized.
After 1 year, Reinaldo has achieved the following goals:
- Goal 1. Identify possible inhibitor candidates by similarity screening of Quinoxaline.The Quinoxaline derivative (ZINC 08382282 saved as sdf file) was used as query molecule to perform a search for similar compounds with FTrees Fragment Space. The Fragment Space Package used was KnowledgeSpace_2.0_20160614 and all the procedure was run on EVOspace-search workflow for KNIME (KNIME Analytics Platform 2.11.3). The node Search FTrees Fragment Space was configurated for several conditions, for example: Number of results were varied from_200 to 1000, and Target similarity was moved from_0.9 to 0.8, Target diversity always was kept in_1.
- Goal 2. Identify plausible binding modes of compounds from goal 1 by docking.For the docking procedure, the receptor node (Prepare Receptor with LeadIT) was charged with the receptor molecule from the enzyme GTF 180 (PDB: 3HZ3). The receptor was prepared according to the default parameters, with a file 3HZ3.fxx previously prepared. In the Receptor Components, only Chain A was included (the unique), then chose the Reference Ligand SUC-1779-A, Chemical Ambiguities were kept as by default. The binding modes of compounds were evaluated with the node Interactive SeeSAR Viewer.
- Goal 3. Identify possible inhibitor candidates from a library of 248 furanic compounds by docking.A library of 248 furanic compounds was inspected in the previous receptor molecule (PDB: 3HZ3), prepared as for goal 2. Around 100 poses of each molecule were analyzed with LeadIT and later visualized with SeeSAR.