The Effect of Ligand-Based Tautomer and Protomer Prediction on Structure-Based Virtual Screening

Kalliokoski, Tuomo; Salo, Heikki S.; Lahtela‐Kakkonen, Maija; Poso, Antti

doi:10.1021/ci900364w

Cited by 62 publications

(57 citation statements)

References 29 publications

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“…Kalliokoski et al [49] argue that similar enrichments in ligand-based screens can be obtained for a reduction in computer time, by using only a single lowest energy tautomer. Given that electrostatic [2,40] to justify the need to consider high energy tautomers in protein-ligand complexes.…”

Section: Do Low Population Tautomers Need To Be Considered In High Thmentioning

confidence: 99%

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Greenwood

Calkins

Sullivan

et al. 2010

J Comput Aided Mol Des

863

608

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Generating the appropriate protonation states of drug-like molecules in solution is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compounds requires a method for determining tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximise enrichment, the lowest energy tautomers must be determined from heterogeneous input, without over-enumerating unfavourable states. While computationally expensive, the density functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett-Taft methodology can very rapidly extrapolate substituent effects from model systems to drug-like molecules via the relationship between pK(T) and pK(a). Combining the two complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited number of measured pK(T) values, especially for the complicated heterocycles often favoured by medicinal chemists for their novelty and versatility. Several hundreds of pre-calculated tautomer energies and substituent pK(a) effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aqueous ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and experimental data. Recommendations are made for how to best incorporate tautomers in molecular design and virtual screening workflows.

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Section: Do Low Population Tautomers Need To Be Considered In High Thmentioning

confidence: 99%

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Greenwood

Calkins

Sullivan

et al. 2010

J Comput Aided Mol Des

863

608

View full text Add to dashboard Cite

show abstract

“…Kalliokoski et al (62) have addressed the same problem by using AutoDock 4 (21) and studying the effect of ligand protonation and tautomerization on 19 targets and the publicly available DUD decoy set. Specifically, they have compared two approaches: enumeration of all protonation and tautomeration ligand forms versus using a single reasonable ligand form.…”

Section: Effect Of Ligand Protonation Tautomerism and Stereoisomerismmentioning

confidence: 99%

Challenges and advances in computational docking: 2009 in review

Yuriev

Agostino

Ramsland

2010

J of Molecular Recognition

306

196

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Docking is a computational technique that places a small molecule (ligand) in the binding site of its macromolecular target (receptor) and estimates its binding affinity. This review addresses methodological developments that have occurred in the docking field in 2009, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. These developments aim to address the main challenges of docking: receptor representation (such aspects as structural waters, side chain protonation, and, most of all, flexibility (from side chain rotation to domain movement)), ligand representation (protonation, tautomerism and stereoisomerism, and the effect of input conformation), as well as accounting for solvation and entropy of binding. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design.

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“…Different protonation was shown to result in alternative binding modes in docking simulations [155]. Another work showed the influence of variations of ligand protonation on the binding energy landscape of proteinligand complexes using a structural consensus that was derived from multiple docking simulations [145].…”

Section: Influence Of Protonation Statesmentioning

confidence: 99%

“…As recently shown, the enumeration of all possible protonation states and the use of all these in the docking is contra-productive. Very often unreasonably highly-charged structures with wrong poses are generated nevertheless obtaining high scores due to the functional forms of today's scoring functions [44,155].…”

Section: Influence Of Ph and Protonation States In Docking Studiesmentioning

confidence: 99%

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

Yunta¹

2014

AJMO

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Protonation states are sometimes crucial for free energy calculations to predict binding ability of molecules to receptors, a main subject for drug design. This mini-review seeks to identify the importance of knowing the influence of pH in such studies to better achieve correct predictions for drug candidates. Protonation states, for both proteins and drugs, need to be considered in docking studies although they have been usually neglected.

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The Effect of Ligand-Based Tautomer and Protomer Prediction on Structure-Based Virtual Screening

Cited by 62 publications

References 29 publications

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution

Challenges and advances in computational docking: 2009 in review

Some Critical Aspects of Molecular Interactions Between Drugs and Receptors

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