Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach

Abstract

Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.

Flavonoids as Putative epi-modulators: Insights into their Binding Mode with BRD4 Bromodomain using Molecular Docking and Dynamics.

“…In this case being the most populated in the MD with amentoflavone. Also, the presence of water bridges with this residue proved significant, a feature recently observed by other groups [66]. Furthermore, this residue is present only on the BRD4 BD1, providing specific contact with histone H3 via hydrogen bonding, an interaction not present with inhibitors such as JQ-1 [69].…”

“…An example of this is Asp145, a contact with amentoflavone with a rather small population. However, this contact has been identified as significant, as it provides ligand stabilization and water network interaction [66].…”

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mproinhibitor

“…When selecting candidates for prospective evaluation, we found that some of the molecules required complicated synthesis. Incorporating into our pipeline a strategy such as DOTS 33,48 , other retrosynthesis algorithms [49][50][51] or even the use of synthetic feasibility scores [52][53][54] , can significantly improve the quality of proposed candidates in the future.…”

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

“…To overcome the problem that SAR by catalog has the limitation to cover only the finite chemical space of commercially available compounds (Hoffer et al, 2018), it is possible to FIGURE 5 | Example of a hot spot analysis using FTMap web server of the oncogenic B-RAF kinase, the target of the first marketed drug from fragment-based drug design, vemurafenib. The surface of the binding site is depicted in gray.…”