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Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling

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Abstract

3-D ligand conformations are required for most ligand-based drug design methods, such as pharmacophore modeling, shape-based screening, and 3-D QSAR model building. Many studies of conformational search methods have focused on the reproduction of crystal structures (i.e. bioactive conformations); however, for ligand-based modeling the key question is how to generate a ligand alignment that produces the best results for a given query molecule. In this work, we study different conformation generation modes of ConfGen and the impact on virtual screening (Shape Screening and e-Pharmacophore) and QSAR predictions (atom-based and field-based). In addition, we develop a new search method, called common scaffold alignment, that automatically detects the maximum common scaffold between each screening molecule and the query to ensure identical coordinates of the common core, thereby minimizing the noise introduced by analogous parts of the molecules. In general, we find that virtual screening results are relatively insensitive to the conformational search protocol; hence, a conformational search method that generates fewer conformations could be considered “better” because it is more computationally efficient for screening. However, for 3-D QSAR modeling we find that more thorough conformational sampling tends to produce better QSAR predictions. In addition, significant improvements in QSAR predictions are obtained with the common scaffold alignment protocol developed in this work, which focuses conformational sampling on parts of the molecules that are not part of the common scaffold.

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Abbreviations

QSAR:

Quantitative structure activity relationship

LBDD:

Ligand-based drug design

AQSAR:

Atom-based QSAR

FQSAR:

Field-based QSAR

NRB :

Average number of rotatable bonds

NSR :

Average number of saturated rings

MCMM/LMOD:

Monte Carlo molecular mechanics and low mode

BEDROC:

Boltzmann-enhanced discrimination of the receiver operating characteristic

EF:

Enrichment factor

RMSD:

Root mean square deviation

CSA:

Common scaffold alignment

PLS:

Partial least-squares

ACE:

Angiotensin-converting enzyme

AChE:

Acetylcholinesterase

ADA:

Adenosine deaminase

ALR2:

Aldose reductase

AmpC:

AmpC β-lactamase

AR:

Androgen receptor

CDK2:

Cyclin-dependent kinase 2

COMT:

Catechol O-methyltransferase

COX1:

Cyclooxygenase-1

COX2:

Cyclooxygenase-2

DHFR:

Dihydrofolate reductase

EGFr:

Epidermal growth factor receptor

ER:

Estrogen receptor

FGFr1:

Fibroblast growth factor receptor kinase

fXa:

Factor Xa

GART:

Glycinamide ribonucleotide transformylase

GPB:

Glycogen phosphorylase β

GR:

Glucocorticoid receptor

HIVpr:

HIV protease

HIVrt:

HIV reverse transcriptase

HMGR:

Hydroxymethylglutaryl-CoA reductase

HSP90:

Human heat shock protein 90

InhA:

Enoyl ACP reductase

MR:

Mineralocorticoid receptor

NA:

Neuraminidase

P38:

P38 mitogen activated protein

PARP:

Poly(ADP-ribose) polymerase

PDE5:

Phosphodiesterase 5

PDGFrb:

Platelet derived growth factor receptor kinase

PNP:

Purine nucleoside phosphorylase

PPAR:

Peroxisome proliferator activated receptor γ

PR:

Progesterone receptor

RXR:

Retinoic X receptor R

SAHH:

S-adenosyl-homocysteine hydrolase

Src:

Tyrosine kinase SRC

TK:

Thymidine kinase

VEGFr2:

Vascular endothelial growth factor receptor

PTP1B:

Protein tyrosine phosphatase 1B

LCK:

Lymphocyte-specific tyrosine kinase

JNK:

c-Jun N-terminal kinase

ERK2:

Extracellular signal-regulated kinase 2

CHK1:

Checkpoint kinase 1

EPHX2:

Cytoplasmic epoxide hydrolase 2

UPA:

Urokinase-type plasminogin activator

DPP4:

Dipeptidyl peptidase IV

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Authors and Affiliations

  1. Schrödinger GmbH, Dynamostr. 13, 68165, Mannheim, Germany

    Daniel Cappel & Jianxin Duan

  2. Schrödinger Inc., 120 W. 45th St., New York, NY, 10036, USA

    Steven L. Dixon & Woody Sherman

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  1. Daniel Cappel
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  2. Steven L. Dixon
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Correspondence to Jianxin Duan.

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Daniel Cappel and Jianxin Duan have contributed equally to this work.

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Cappel, D., Dixon, S.L., Sherman, W. et al. Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling. J Comput Aided Mol Des 29, 165–182 (2015). https://doi.org/10.1007/s10822-014-9813-4

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