Poster presentation at the 2017 Groupe de Graphisme & Modélisation Moléculaire conference (Reims, France):
Fast software development in drug design with the C2P-API toolkit : Rebuilding ligand bound conformation from PDB subpocket superpositions
Abstract: Literature in the FBDD field reported cases where the binding location and orientation of small co-crystallized fragments is preserved when these fragments are chemically evolved into larger ligands. Crystallography also revealed the central role of some weak fragment binders. With the benefit of the PDB growth, pocket superposition illustrated some ligand substructures having conserved binding modes towards multiple targets. Recently, we showed that 48% of 2,241 ligands structures uniquely represented in the PDB could be reproduced at 80 % of their atom coordinates within a 1.0 Å deviation by using chemical material from 3D pocket superpositions.
The development of an heuristic to rebuild ligand bound conformation from PDB pocket superpositions requires at least methods to detect Maximum Common Substructures between the compound to 3D-rebuild and all PDB ligands from superposed pockets, and methods to 3D-hybridise those MCS fragments. It was possible to develop a rebuilder prototype including a graphical interface in about 3 months by combining (a) the richness of the C2P-API Chemo-Proteomic Advanced Programming Interface, (b) the agility of the .Net C# language including reconfigurable dictionaries to include molecular rules, quasi-automatic parallelization and safe memory management, and (c) the comfort of the Microsoft Visual Studio Community IDE in developing graphical interface and debugging software.
Our auto-converging knowledge-based iterative hybridiser software is 3D-rebuilding as much as possible any input 2D-ligands into any biostructural binding site. We selected inhibitors co-crystallized in multiple PDB proteins to validate our protocol.
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