  Most earlier 3D structure-based molecular generation approaches follow an
atom-wise paradigm, incrementally adding atoms to a partially built molecular
fragment within protein pockets. These methods, while effective in designing
tightly bound ligands, often overlook other essential properties such as
synthesizability. The fragment-wise generation paradigm offers a promising
solution. However, a common challenge across both atom-wise and fragment-wise
methods lies in their limited ability to co-design plausible chemical and
geometrical structures, resulting in distorted conformations. In response to
this challenge, we introduce the Deep Geometry Handling protocol, a more
abstract design that extends the design focus beyond the model architecture.
Through a comprehensive review of existing geometry-related models and their
protocols, we propose a novel hybrid strategy, culminating in the development
of FragGen - a geometry-reliable, fragment-wise molecular generation method.
FragGen marks a significant leap forward in the quality of generated geometry
and the synthesis accessibility of molecules. The efficacy of FragGen is
further validated by its successful application in designing type II kinase
inhibitors at the nanomolar level.
