Enthalpic efficiency of ligand binding

G. Ferenczy, György M. Keseru

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The thermodynamics of ligand-protein binding has received much attention recently. In the present contribution we focus on the enthalpic component of binding. The dissociation constant, pKd, was decomposed into enthalpic and entropic components (pKd = pKH + pK S), and pKH, defined as pKH = -ΔH/(2.303•RT) was used to characterize the enthalpy contribution to binding. It was found that the maximal achievable pKH decreases with increasing molecular size. This is in contrast to maximal pKd that increases with molecular size until it achieves a plateau. Size-independent enthalpic efficiency (SIHE) was defined as SIHE = pKH/40•HA 0.3, with HA being the number of heavy atoms. SIHE allows a size unbiased comparative binding characterization of compounds. It can find use in hit and lead selection and also in monitoring optimization in drug discovery programs. The physical background of decreasing maximal pKH with molecular size is discussed, and its consequences to drug discovery are analyzed. It is concluded that the feasibility of simultaneous optimization of affinity and enthalpy diminishes with increasing molecular size. Consequently, binding thermodynamics considerations are to be applied primarily in hit prioritization and hit-to-lead optimization.

Original languageEnglish
Pages (from-to)1536-1541
Number of pages6
JournalJournal of Chemical Information and Modeling
Volume50
Issue number9
DOIs
Publication statusPublished - Sep 27 2010

Fingerprint

Ligands
efficiency
Enthalpy
Thermodynamics
drug
Lead
monitoring
Atoms
Monitoring
present
Drug Discovery
Protein Binding

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Enthalpic efficiency of ligand binding. / Ferenczy, G.; Keseru, György M.

In: Journal of Chemical Information and Modeling, Vol. 50, No. 9, 27.09.2010, p. 1536-1541.

Research output: Contribution to journalArticle

Ferenczy, G. ; Keseru, György M. / Enthalpic efficiency of ligand binding. In: Journal of Chemical Information and Modeling. 2010 ; Vol. 50, No. 9. pp. 1536-1541.
@article{7f72db3671e24fd285b743d113fc9aee,
title = "Enthalpic efficiency of ligand binding",
abstract = "The thermodynamics of ligand-protein binding has received much attention recently. In the present contribution we focus on the enthalpic component of binding. The dissociation constant, pKd, was decomposed into enthalpic and entropic components (pKd = pKH + pK S), and pKH, defined as pKH = -ΔH/(2.303•RT) was used to characterize the enthalpy contribution to binding. It was found that the maximal achievable pKH decreases with increasing molecular size. This is in contrast to maximal pKd that increases with molecular size until it achieves a plateau. Size-independent enthalpic efficiency (SIHE) was defined as SIHE = pKH/40•HA 0.3, with HA being the number of heavy atoms. SIHE allows a size unbiased comparative binding characterization of compounds. It can find use in hit and lead selection and also in monitoring optimization in drug discovery programs. The physical background of decreasing maximal pKH with molecular size is discussed, and its consequences to drug discovery are analyzed. It is concluded that the feasibility of simultaneous optimization of affinity and enthalpy diminishes with increasing molecular size. Consequently, binding thermodynamics considerations are to be applied primarily in hit prioritization and hit-to-lead optimization.",
author = "G. Ferenczy and Keseru, {Gy{\"o}rgy M.}",
year = "2010",
month = "9",
day = "27",
doi = "10.1021/ci100125a",
language = "English",
volume = "50",
pages = "1536--1541",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - Enthalpic efficiency of ligand binding

AU - Ferenczy, G.

AU - Keseru, György M.

PY - 2010/9/27

Y1 - 2010/9/27

N2 - The thermodynamics of ligand-protein binding has received much attention recently. In the present contribution we focus on the enthalpic component of binding. The dissociation constant, pKd, was decomposed into enthalpic and entropic components (pKd = pKH + pK S), and pKH, defined as pKH = -ΔH/(2.303•RT) was used to characterize the enthalpy contribution to binding. It was found that the maximal achievable pKH decreases with increasing molecular size. This is in contrast to maximal pKd that increases with molecular size until it achieves a plateau. Size-independent enthalpic efficiency (SIHE) was defined as SIHE = pKH/40•HA 0.3, with HA being the number of heavy atoms. SIHE allows a size unbiased comparative binding characterization of compounds. It can find use in hit and lead selection and also in monitoring optimization in drug discovery programs. The physical background of decreasing maximal pKH with molecular size is discussed, and its consequences to drug discovery are analyzed. It is concluded that the feasibility of simultaneous optimization of affinity and enthalpy diminishes with increasing molecular size. Consequently, binding thermodynamics considerations are to be applied primarily in hit prioritization and hit-to-lead optimization.

AB - The thermodynamics of ligand-protein binding has received much attention recently. In the present contribution we focus on the enthalpic component of binding. The dissociation constant, pKd, was decomposed into enthalpic and entropic components (pKd = pKH + pK S), and pKH, defined as pKH = -ΔH/(2.303•RT) was used to characterize the enthalpy contribution to binding. It was found that the maximal achievable pKH decreases with increasing molecular size. This is in contrast to maximal pKd that increases with molecular size until it achieves a plateau. Size-independent enthalpic efficiency (SIHE) was defined as SIHE = pKH/40•HA 0.3, with HA being the number of heavy atoms. SIHE allows a size unbiased comparative binding characterization of compounds. It can find use in hit and lead selection and also in monitoring optimization in drug discovery programs. The physical background of decreasing maximal pKH with molecular size is discussed, and its consequences to drug discovery are analyzed. It is concluded that the feasibility of simultaneous optimization of affinity and enthalpy diminishes with increasing molecular size. Consequently, binding thermodynamics considerations are to be applied primarily in hit prioritization and hit-to-lead optimization.

UR - http://www.scopus.com/inward/record.url?scp=77957237209&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957237209&partnerID=8YFLogxK

U2 - 10.1021/ci100125a

DO - 10.1021/ci100125a

M3 - Article

C2 - 20684566

AN - SCOPUS:77957237209

VL - 50

SP - 1536

EP - 1541

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 9

ER -