Break Down in Order To Build Up: Decomposing Small Molecules for Fragment-Based Drug Design with eMolFrag

Abstract

Constructing high-quality libraries of molecular building blocks is essential for successful fragment-based drug discovery. In this communication, we describe eMolFrag, a new open-source software to decompose organic compounds into nonredundant fragments retaining molecular connectivity information. Given a collection of molecules, eMolFrag generates a set of unique fragments comprising larger moieties, bricks, and smaller linkers connecting bricks. These building blocks can subsequently be used to construct virtual screening libraries for targeted drug discovery. The robustness and computational performance of eMolFrag is assessed against the Directory of Useful Decoys, Enhanced database conducted in serial and parallel modes with up to 16 computing cores. Further, the application of eMolFrag in de novo drug design is illustrated using the adenosine receptor. eMolFrag is implemented in Python, and it is available as stand-alone software and a web server at and .

Chemical Space Expansion of Bromodomain Ligands Guided by in Silico Virtual Couplings (AutoCouple)

“…Success in high-throughput screening ultimately relies on the screening library: 5 − 7 the exploration of chemical space that is not biased toward already investigated targets is decisive not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against protein targets that are hard-to-drug. 8 − 11 Classical de novo strategies can potentially populate new areas of chemical space, 12 − 16 and thus, programs have been developed to disconnect molecules following retrosynthesis rules 17 , 18 producing fragments that can be used later on to construct new libraries. 19 Nevertheless, significant challenges when reaching the synthesis stage might prevent those new molecular entities from being prepared and, ultimately, becoming useful chemical probes.…”

Consensus queries in ligand-based virtual screening experiments

“…This experiment simulates an in silico combinatorial chemistry library enumeration [ 18 , 33 – 36 ], where molecules are generated, fingerprinted and scored on the fly. The virtual screen is stopped after some amount of time, not because the immense library enumeration has finished.…”

Rise of Virtual Drug Design Tools

“…The search refined to the publication year between 2007 and 2017 ended up with the 986 references including 21 patents, clearly showed that there was a real progress happened in this area over the past fifteen years involving the FBDD concept. Recently, there are a number virtual screening/drug design tools available to develop the chemical leads/drugs candidates [5,6].…”