KinaFrag explores the kinase-ligand fragment interaction space for selective kinase inhibitor discovery

Protein kinases play a crucial role in many cellular signaling processes, making them one of the most important families of drug targets. But selectivity put a barrier at the design of kinase inhibitors. Fragment-based drug design strategies have been successfully applied to develop novel selective kinase inhibitors. However, the complicate kinase-fragment interaction and fragment-to-lead process pose challenges to fragment-based kinase discovery. Here, we developed a web source KinaFrag to investigate kinase-fragment interaction space and perform fragment-to-lead optimization. KinaFrag contained 31464 fragments from reported kinase inhibitors, which involved 3244 crystal fragment structures and 7783 crystal kinase-fragment complexes. These crystal fragments were classified by their binding cleft and subpockets, and their 3D structure and interactions were displayed in KinaFrag. In addition, the structural information, physicochemical information, similarity information, and substructure relationship information were contained in KinaFrag. Moreover, a computational fragment growing strategy obviously developed by our group was implemented in the KinaFrag. We test this fragment growing strategy using our fragment libraries, and obtained a lead compound of c-Met with ~1000-fold in vitro activity improvement compared with the hit compound. We hope KinaFrag could become a powerful tool for the fragment-based kinase inhibitor design. KinaFrag is freely available at http://chemyang.ccnu.edu.cn/ccb/database/KinaFrag/.

Fragment Molecular Orbital Based Interaction Analyses on Complexes Between RBD Variants and ACE2

The spike protein plays an important role in the infection of SARS-CoV-2 to human cells, and the binding affinity of receptor binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) is of special interest. In this report, we present a series of interaction analyses for the RBD - ACE2 complex (PDB ID: 6M0J) and mutated complexes of UK (B.1.1.7 lineage), South Africa (B1.351) and Brazil (B1.1.248) types, based on the fragment molecular orbital (FMO) calculations. The effects of mutations are investigated in terms of inter-fragment interaction energies (IFIEs), indicating the higher affinities of RBD variants with ACE2.

Fragment Molecular Orbital Based Interaction Analyses on Complexes Between RBD Variants and ACE2

The spike protein plays an important role in the infection of SARS-CoV-2 to human cells, and the binding affinity of receptor binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) is of special interest. In this report, we present a series of interaction analyses for the RBD - ACE2 complex (PDB ID: 6M0J) and mutated complexes of UK (B.1.1.7 lineage), South Africa (B1.3.51) and Brazil (B1.1.248) types, based on the fragment molecular orbital (FMO) calculations. The effects of mutations are investigated in terms of inter-fragment interaction energies (IFIEs), indicating the higher affinities of RBD variants with ACE2.

Fragment Molecular Orbital Based Interaction Analyses on Complexes Between RBD Variants and ACE2

The spike protein plays an important role in the infection of SARS-CoV-2 to human cells, and the binding affinity of receptor binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) is of special interest. In this report, we present a series of interaction analyses for the RBD - ACE2 complex (PDB ID: 6M0J) and mutated complexes of UK (B.1.1.7 lineage), South Africa (B1.3.51) and Brazil (B1.1.248) types, based on the fragment molecular orbital (FMO) calculations. The effects of mutations are investigated in terms of inter-fragment interaction energies (IFIEs), indicating the higher affinities of RBD variants with ACE2.