BIBuilder: Exhaustive Searching for De Novo Ligands

Abstract

The de novo design program BIBuilder has been developed for structure-based as well as ligand-based design. Incremental growth allows for the de novo design of novel molecules with putative bioactivity. In addition, linking between existing fragments enables scaffold hopping tasks. A RECAP-based retrosynthetic fragment connection protocol yields ligands that are synthesizable. An exhaustive fragment search protocol assures that known ligands are always found if all necessary fragments exist in the database of building blocks. To make an exhaustive search possible, a strategy of connecting tens of thousands of unique fragments with only three growth or linking steps is adopted resulting in the generation of up to 10(16) possible compounds with up to 10(21) conformations. Ligands are scored by shape and pharmacophore matches that can be individually weighted. Final hits are evaluated through customizable scoring functions. Estrogen receptor, COX-2, renin, and NNRTI examples illustrate the performance of BIBuilder in different tasks such as structure-based or ligand-based growing and linking. Not only are known ligands reproduced in all test cases but a number of interesting alternative scaffolds and ligands have been found.

De Novo Design at the Edge of Chaos

“…This scaffold-hopping method has led to the discovery of NCEs with the desired biochemical and pharmacological effects . Moreover, the design concept is implemented in several related programs (e.g., TOPAS, BI Builder) and together with other receptor- and ligand-based tools − provides a broad choice of working methods for idea generation in drug discovery. Figure shows selected examples of de novo designed compounds from recent publications ( 5 ; 6 , 10 ; 7 ; 8 ; 9 ; 11 ; 12 ; , 13 ; 14 ; 15 ; 16 ; 17 ).…”

Automated Design of Realistic Organometallic Molecules from Fragments

“…61,63,75,76,92 Alternatively, SMILES and 2D graphs have been used to represent only the molecular structure of the building blocks, i.e., the content of the vertices, while a dedicated data structure defined the surrounding graph-like chromosome. 30,73,91,118,119 The analogous strategy with 3D representation has been used, 58,66,74,88,[120][121][122] but mostly in connection to fragment-based drug discovery, 123 which should not be confused with the fragment-based building strategy introduced above, although the latter is usually implemented as part of the former. 78 With an alternative use of graphs, the construction and modification of molecules can be seen as a short walk on a graph that spans all possible fragments and connections.…”

Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

“…It consists of an ensemble of 3D stereoelectronic features shared by well-known active compounds and, hence, necessary to ensure a favorable interaction with a particular biological target of interest (Wallach, 2011;Sanders et al, 2012). Intriguingly, despite the increasing number of examples for pharmacophore modeling or FBDD reported in the last two decades, the implications of a combined implementation of these approaches have been poorly discussed and analyzed, except for a couple of research works published by (Teodoro and Muegge, 2011;Fechner and Schneider, 2007), respectively. However, we believe that several key aspects still remain unresolved.…”