Submission Details

Design Rationale:

Molecular modeling was performed using the Quantum-Based Structure Builder (QSB) module. This module consists of two functional parts. The first provides pharmacophore-based mapping of targeted cavity by molecular fragments (probes) with their further minimization. The second subprogram provides step-by-step linking of building blocks to the probes, taking into account the protein environment. Since ligands of crystal structures acted as initial probes in current experiment, only the second part of QSB module was used. As starting molecule, ligand from 5REL crystal was used. Model was built based on protein structure from 6LU7 crystal. Libraries of building blocks were obtained by fragmentation of molecules from Enamine 10K diverse collection with BRICS algorithm. Five stages of structure building have been completed. In the first two stages, libraries of larger fragments (linkers) were used in order to extend the scaffold structure. At each of these two consecutive steps, the top 20 structures were selected by the module based on calculated energy values and then the top 5 of them were selected for further calculations based on expert evaluation. The next 3 stages were aimed at linking small functional groups and were performed automatically. During the first two stages the 5 best structures were automatically selected for the next step. At the final step, the 20 best structures in terms of energy were retained.

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