The critical role of QM/MM X-ray refinement and accurate tautomer/protomer determination in structure-based drug design

Autor: Oleg Y. Borbulevych, Roger I. Martin, Lance M. Westerhoff
Rok vydání: 2020
Předmět:
Models
Molecular
ONIOM
Protein Conformation
Quantum mechanics X-ray refinement
Context (language use)
Protomer
Crystallography
X-Ray
Ligand strain
01 natural sciences
Article
Small Molecule Libraries
QM/MM
tautomers
03 medical and health sciences
Isomerism
0103 physical sciences
Drug Discovery
Humans
difference density Z-score
Statistical physics
Physical and Theoretical Chemistry
Databases
Protein
high throughput crystallography
X-ray crystallography
030304 developmental biology
Energy functional
Pharmacology
Physics
0303 health sciences
Binding Sites
010304 chemical physics
Structure guided drug discovery
Proteins
CSAR set
Computer Science Applications
Characterization (materials science)
Bond length
Structure-based drug discovery
Pharmaceutical Preparations
Structural biology
Drug Design
Quantum Theory
protonation states
Zdroj: Journal of Computer-Aided Molecular Design
ISSN: 1573-4951
0920-654X
DOI: 10.1007/s10822-020-00354-6
Popis: Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule—along with any bound ligand(s)—within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method—coupled with our XModeScore method for experimental tautomer/protomer state determination—to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields. Electronic supplementary material The online version of this article (10.1007/s10822-020-00354-6) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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