FlexNovo: Structure‐Based Searching in Large Fragment Spaces

Abstract

We present a new molecular design program, FlexNovo, for structure-based searching within large fragment spaces following a sequential growth strategy. The fragment spaces consist of several thousands of chemical fragments and a corresponding set of rules that specify how the fragments can be connected. FlexNovo is based on the FlexX molecular docking software and makes use of its incremental construction algorithm and the underlying chemical models. Interaction energies are calculated by using standard scoring functions. Several placement geometry, physicochemical property (drug-likeness), and diversity filter criteria are directly integrated into the "build-up" process. FlexNovo has been used to design potential inhibitors for four targets of pharmaceutical interest (dihydrofolate reductase, cyclin-dependant kinase 2, cyclooxygenase-2, and the estrogen receptor). We have carried out calculations using different diversity parameters for each of these targets and generated solution sets containing up to 50 molecules. The compounds obtained show that FlexNovo is able to generate a diverse set of reasonable molecules with drug-like properties. The results, including an automated similarity analysis with the Feature Tree program, indicate that FlexNovo often reproduces structural motifs as well as the corresponding binding modes seen in known active structures.

BIBuilder: Exhaustive Searching for De Novo Ligands

“…In fact the same example has been used by other programs to illustrate de novo design capabilities. [13] Especially due to the limited number of growth steps allowed in BIBuilder, we have considered estrogen receptor to be a revealing test case. Figure 13 illustrates the BIBuilder query setup that was used to search for putative ER ligands.…”

“…[13,15] To illustrate the plausibility of such potential, we estimated synthesizability by using the rsynth score in MOE [33] ( Table 4). The rsynth score varies between 0 and 1 with increasing potential synthesizability.…”

“…[11,12] More recently, programs such as FlexNovo use similar construction principles involving fragments. [13] Enabling structure-based as well as ligand-based growing and linking we opted for a shape and pharmacophore match-driven primary scoring function followed by minimization and customizable scoring of hits. After each exhaustively enumerated intermediate growth step a customizable pharmacophore score threshold prunes the solution space for further growth.…”

Second-generation de novo design: a view from a medicinal chemist perspective

“…Fragment docking within a protein cavity has been long seen as a viable option for de novo design approaches [1]. Experimental fragment-based drug discovery (FBDD) showed that fragment binding, when properly combined with structure-based drug design (SBDD), leads to the successful identification of promising leads [2].…”

“…Starting from the basic assumption that scoring functions are accurate enough to predict correct fragment positioning within protein cavities [1,3], we investigated computational routes to generate fragments and recombine them without losing the chemical and geometric information of parent bond vectors. At the same time, we tried to integrate our current synthetic knowledge into the process.…”