6BLN

BTK complex with compound 13

Summary for 6BLN

• Entry DOI: 10.2210/pdb6bln/pdb
• Related: 6AUA 6AUB 6BIK 6BKE 6BKH 6BKW 6EP9
• Descriptor: Tyrosine-protein kinase BTK, SULFATE ION, N-(3-{5-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}-2,6-difluorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide, ... (5 entities in total)
• Functional Keywords: btk, inhibitor, water structure, kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34755.54

Authors

Kiefer, J.R.,Eigenbrot, C.,Yu, C.L. (deposition date: 2017-11-10, release date: 2018-11-07, Last modification date: 2019-03-27)

Primary citation

Nittinger, E.,Gibbons, P.,Eigenbrot, C.,Davies, D.R.,Maurer, B.,Yu, C.L.,Kiefer, J.R.,Kuglstatter, A.,Murray, J.,Ortwine, D.F.,Tang, Y.,Tsui, V.
Water molecules in protein-ligand interfaces. Evaluation of software tools and SAR comparison.
J. Comput. Aided Mol. Des., 33:307-330, 2019

PubMed Abstract: Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton's Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.

PubMed: 30756207
DOI: 10.1007/s10822-019-00187-y

Experimental method

X-RAY DIFFRACTION (1.3 Å)