Computational and Experimental Studies of Inhibitor Design for Aldolase A

Rui Qi, Brandon Walker, Zhifeng Jing, Maiya Yu, Gabriel Stancu, Ramakrishna Edupuganti, Kevin Dalby, Pengyu Ren

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Glycolytic enzyme fructose-bisphosphate aldolase A is an emerging therapeutic target in cancer. Recently, we have solved the crystal structure of murine aldolase in complex with naphthalene-2,6-diyl bisphosphate (ND1) that served as a template of the design of bisphosphate-based inhibitors. In this work, a series of ND1 analogues containing difluoromethylene (-CF2), methylene (-CH2), or aldehyde substitutions were designed. All designed compounds were studied using molecular dynamics (MD) simulations with the AMOEBA force field. Both energetics and structural analyses have been done to understand the calculated binding free energies. The average distances between ligand and protein atoms for ND1 were very similar to those for the ND1 crystal structure, which indicates that our MD simulation is sampling the correct conformation well. CF2 insertion lowers the binding free energy by 10-15 kcal/mol, while CF2 substitution slightly increases the binding free energy, which matches the experimental measurement. In addition, we found that NDB with two CF2 insertions, the strongest binder, is entropically driven, while others including NDA with one CF2 insertion are all enthalpically driven. This work provides insights into the mechanisms underlying protein-phosphate binding and enhances the capability of applying computational and theoretical frameworks to model, predict, and design diagnostic strategies targeting cancer.

Original languageEnglish (US)
Pages (from-to)6034-6041
Number of pages8
JournalJournal of Physical Chemistry B
Volume123
Issue number28
DOIs
StatePublished - Jun 21 2019

Fingerprint

aldolase
Fructose-Bisphosphate Aldolase
inhibitors
Free energy
insertion
Molecular dynamics
free energy
Phosphate-Binding Proteins
Substitution reactions
Crystal structure
Proteins
Fructose
cancer
Computer simulation
substitutes
Naphthalene
molecular dynamics
proteins
Aldehydes
crystal structure

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Qi, R., Walker, B., Jing, Z., Yu, M., Stancu, G., Edupuganti, R., ... Ren, P. (2019). Computational and Experimental Studies of Inhibitor Design for Aldolase A. Journal of Physical Chemistry B, 123(28), 6034-6041. https://doi.org/10.1021/acs.jpcb.9b04551

Computational and Experimental Studies of Inhibitor Design for Aldolase A. / Qi, Rui; Walker, Brandon; Jing, Zhifeng; Yu, Maiya; Stancu, Gabriel; Edupuganti, Ramakrishna; Dalby, Kevin; Ren, Pengyu.

In: Journal of Physical Chemistry B, Vol. 123, No. 28, 21.06.2019, p. 6034-6041.

Research output: Contribution to journalArticle

Qi, R, Walker, B, Jing, Z, Yu, M, Stancu, G, Edupuganti, R, Dalby, K & Ren, P 2019, 'Computational and Experimental Studies of Inhibitor Design for Aldolase A', Journal of Physical Chemistry B, vol. 123, no. 28, pp. 6034-6041. https://doi.org/10.1021/acs.jpcb.9b04551
Qi, Rui ; Walker, Brandon ; Jing, Zhifeng ; Yu, Maiya ; Stancu, Gabriel ; Edupuganti, Ramakrishna ; Dalby, Kevin ; Ren, Pengyu. / Computational and Experimental Studies of Inhibitor Design for Aldolase A. In: Journal of Physical Chemistry B. 2019 ; Vol. 123, No. 28. pp. 6034-6041.
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