In silico construction of a focused fragment library facilitating exploration of chemical space**

Abstract

AbstractFragment‐based drug design (FBDD) has emerged as a captivating subject in the realm of computer‐aided drug design, enabling the generation of novel molecules through the rearrangement of ring systems within known compounds. The construction of focused fragment library plays a pivotal role in FBDD, necessitating the compilation of all potential bioactive ring systems capable of interacting with a specific target. In our study, we propose a workflow for the development of a focused fragment library and combinatorial compound library. The fragment library comprises seed fragments and collected fragments. The extraction of seed fragments is guided by receptor information, serving as a prerequisite for establishing a focused libraries. Conversely, collected fragments are obtained using the feature graph method, which offers a simplified representation of fragments and strikes a balance between diversity and similarity when categorizing different fragments. The utilization of feature graph facilitates the rational partitioning of chemical space at fragment level, enabling the exploration of desired chemical space and enhancing the efficiency of screening compound library. Analysis demonstrates that our workflow enables the enumeration of a greater number of entirely new potential compounds, thereby aiding in the rational design of drugs.