Journal of Computer-Aided Molecular Design

, Volume 25, Issue 1, pp 1–12

Challenges in the determination of the binding modes of non-standard ligands in X-ray crystal complexes

Perspective

DOI: 10.1007/s10822-010-9397-6

Cite this article as:
Malde, A.K. & Mark, A.E. J Comput Aided Mol Des (2011) 25: 1. doi:10.1007/s10822-010-9397-6

Abstract

Despite its central role in structure based drug design the determination of the binding mode (position, orientation and conformation in addition to protonation and tautomeric states) of small heteromolecular ligands in protein:ligand complexes based on medium resolution X-ray diffraction data is highly challenging. In this perspective we demonstrate how a combination of molecular dynamics simulations and free energy (FE) calculations can be used to correct and identify thermodynamically stable binding modes of ligands in X-ray crystal complexes. The consequences of inappropriate ligand structure, force field and the absence of electrostatics during X-ray refinement are highlighted. The implications of such uncertainties and errors for the validation of virtual screening and fragment-based drug design based on high throughput X-ray crystallography are discussed with possible solutions and guidelines.

Keywords

X-ray crystallographyLigand designMolecular dynamics simulationsFree energy calculationsBinding mode

Abbreviations

aaRSs

Aminoacyl-tRNA synthetases

ATB

Automated Topology Builder

CDK

Cyclin Depdendent Kinase

CNS

Crystallography and NMR System

CR6

1-deoxy-1-acetylamino-β-d-gluco-2-heptulopyranosonamide

FE

Free Energy

GLG

α-d-glucopyranosyl-2-carboxamide

GPb

Glycogen Phosphorylase b

HIV-1

Human Immunodeficiency Virus-1

JG-365

Ac-Ser-Leu-Asn-Phe-Ψ[CH(OH)CH2N]-Pro-Ile-Val-OMe

L-Ser

L-Serine

LIGA

(4-{4H-indeno[1,2-c]pyrazol-3-yl}pyridine)

LIGB

(4-{1H,4H-indeno[1,2-c]pyrazol-3-yl}pyridine)

MD

Molecular Dynamics

MM

Molecular Mechanics

Pab-NTD

N-terminal editing domain of Pyrococcus abyssi threonyl-tRNA synthetase

PDB

Protein Data Bank

PDE4B

Phosphodiesterase 4B

PNMT

Phenylethanolamine N-methyltransferase

QM

Quantum Mechanics

ROL

Rolipram

SC558

1-phenylsulfonamide-3-trifluoromethyl-5-p-bromophenylpyrazole

SKF

1,2,3,4-tetrahydro-isoquinoline-7-sulphonicacidamide

TetR

Tet repressor protein

Supplementary material

10822_2010_9397_MOESM1_ESM.doc (67 kb)
Supplementary material 1 (DOC 67 kb)

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.School of Chemistry and Molecular BiosciencesUniversity of QueenslandSt. LuciaAustralia
  2. 2.Institute for Molecular BioscienceUniversity of QueenslandSt. LuciaAustralia