Combining docking-based comparative intermolecular contacts analysis and k-nearest neighbor correlation for the discovery of new check point kinase 1 inhibitors

Abstract

Check point kinase 1 (Chk1) is an important protein in G2 phase checkpoint arrest required by cancer cells to maintain cell cycle and to prevent cell death. Therefore, Chk1 inhibitors should have potential as anti-cancer therapeutics. Docking-based comparative intermolecular contacts analysis (dbCICA) is a new three-dimensional quantitative structure activity relationship method that depends on the quality and number of contact points between docked ligands and binding pocket amino acid residues. In this presented work we implemented a novel combination of k-nearest neighbor/genetic function algorithm modeling coupled with dbCICA to select critical ligand-Chk1 contacts capable of explaining anti-Chk1 bioactivity among a long list of inhibitors. The finest set of contacts were translated into two valid pharmacophore hypotheses that were used as 3D search queries to screen the National Cancer Institute's structural database for new Chk1 inhibitors. Three potent Chk1 inhibitors were discovered with IC50 values ranging from 2.4 to 69.7 µM.

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

“…To understand the interactions associated in ligand binding into Aurora-A kinase, we implemented the innovative structure-based 3D-QSAR methodology; docking-based comparative intermolecular contacts analysis (dbCICA) [51,56,57,[60][61][62][63][64][65][66][67] as a tool to study how the seventy-nine Aurora-A kinase inhibitors (Table S1 in Supplementary Material) bind into Aurora-A binding pocket. dbCICA modeling was used to create successful pharmacophore hypotheses that highlighted the critical binding interactions engaged in ligand-Aurora-A kinase binding.…”

“…The fundamental use of pharmacophores models is the discovery of new chemical scaffolds demonstrating similar biological characteristics or scaffold hopping [56][57][58][59][60][61][62][63][64][65][83][84][85]. Therefore, Refined-Hypo (SB-1) pharmacophore (Figure 2) was used as a 3D query to search and screen the NCI list of compounds for new Aurora-A kinase inhibitors with novel chemotypes.…”

“…The resulting docked poses (i.e., of hits) were analyzed to identify their binding critical contacts. The activity of each hit was predicted by using the sums of critical contacts as identified by the respective dbCICA model (Tables 1 and 2) through substituting the sum of contacts with binding-site atoms in the corresponding dbCICA-regression equations [56,57,[60][61][62][63][64][65][66][67].…”

“…At last, pharmacophores are used for in silico database searching, aiming to find novel hits [51,56,57,[60][61][62][63][64][65][66][67].…”

“…dbCICA was applied previously to discover new heat shock protein 90 inhibitors, new glycogen phosphorylase inhibitors, new fungal N-myristoyl transferase inhibitors, new CPK1 inhibitors, new FGFR1 inhibitors, new 3CLpro inhibitors, new Acetylcholinesterase inhibitors, new Gyrase b, new Flt3 and lately new JNK3 inhibitors [51][52][53][54][55][56][57][60][61][62][63][64][65][66][67].…”