The conformational landscape of three FK506-related drugs with disparate inhibition constants is determined in bulk solution using a replica exchange simulation method with solute torsional tempering. Energetic fitness of important drug conformations with respect to the FKBP12 protein is evaluated by molecular mechanics. Results show that the experimental affinity toward peptidyl−prolyl cis−trans isomerase protein (FKBP12) of the analyzed ligands appears to be positively correlated to the observed population of specific chair structures of the drug piperidinic ring in bulk solution. This observation is rationalized on the basis that such structures, stabilized by stereospecific intramolecular hydrophobic interactions, allows the formation of a pair of protein−ligand hydrogen bonds upon binding.

Intraligand Hydrophobic Interactions Rationalize Drug Affinities for Peptidyl−Prolyl Cis−Trans Isomerase Protein / Marco Bizzarri; Simone Marsili; Piero Procacci. - In: JOURNAL OF PHYSICAL CHEMISTRY. B, CONDENSED MATTER, MATERIALS, SURFACES, INTERFACES & BIOPHYSICAL. - ISSN 1520-6106. - STAMPA. - 115:(2011), pp. 6193-6201. [10.1021/jp110585p]

Intraligand Hydrophobic Interactions Rationalize Drug Affinities for Peptidyl−Prolyl Cis−Trans Isomerase Protein

BIZZARRI, MARCO;MARSILI, SIMONE;PROCACCI, PIERO
2011

Abstract

The conformational landscape of three FK506-related drugs with disparate inhibition constants is determined in bulk solution using a replica exchange simulation method with solute torsional tempering. Energetic fitness of important drug conformations with respect to the FKBP12 protein is evaluated by molecular mechanics. Results show that the experimental affinity toward peptidyl−prolyl cis−trans isomerase protein (FKBP12) of the analyzed ligands appears to be positively correlated to the observed population of specific chair structures of the drug piperidinic ring in bulk solution. This observation is rationalized on the basis that such structures, stabilized by stereospecific intramolecular hydrophobic interactions, allows the formation of a pair of protein−ligand hydrogen bonds upon binding.
2011
115
6193
6201
Marco Bizzarri; Simone Marsili; Piero Procacci
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/428498
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 10
social impact