title: Identification of ligand efficient, fragment-like hits from an HTS library: structure-based virtual screening and docking investigations of 2H- and 3H-pyrazolo tautomers for Aurora kinase A selectivity.
abstract: Furanopyrimidine 1 (IC50 = 273 nM, LE = 0.36, LELP = 10.28) was recently identified by high-throughput screening (HTS) of an in-house library (125,000 compounds) as an Aurora kinase inhibitor. Structure-based hit optimization resulted in lead molecules with in vivo efficacy in a mouse tumour xenograft model, but no oral bioavailability. This is attributed to "molecular obesity", a common problem during hit to lead evolution during which degradation of important molecular properties such as molecular weight (MW) and lipophilicity occurs. This could be effectively tackled by the right choice of hit compounds for optimization. In this regard, ligand efficiency (LE) and ligand efficiency dependent lipophilicity (LELP) indices are more often used to choose fragment-like hits for optimization. To identify hits with appropriate LE, we used a MW cut-off <250, and pyrazole structure to filter HTS library. Next, structure-based virtual screening using software (Libdock and Glide) in the Aurora A crystal structure (PDB ID: 3E5A) was carried out, and the top scoring 18 compounds tested for Aurora A enzyme inhibition. This resulted in the identification of a novel tetrahydro-pyrazolo-isoquinoline hit 7 (IC50 = 852 nM, LE = 0.44, LELP = 8.36) with fragment-like properties suitable for further hit optimization. Moreover, hit 7 was found to be selective for Aurora A (Aurora B IC50 = 35,150 nM) and the possible reasons for selectivity investigated by docking two tautomeric forms (2H- and 3H-pyrazole) of 7 in Auroras A and B (PDB ID: 4AF3) crystal structures. This docking study shows that the major 3H-pyrazole tautomer of 7 binds in Aurora A stronger than in Aurora B.
authors.affiliation: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, 605014, Puducherry, India.
authors.forename: Sailu
authors.initials: S
authors.lastname: Sarvagalla
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Singh
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Ke
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: John T A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D064096:Aurora Kinase A