spacer
spacer

PDBsum entry 2pk5
Go to PDB code: 
protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
2pk5

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
99 a.a. *
Ligands
075
GOL
Waters ×241
* Residue conservation analysis
PDB id:
2pk5
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of HIV-1 protease (q7k, l33i, l63i ) in complex with kni-10075
Structure: Protease. Chain: a, b. Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: subtype b. Gene: gag-pol. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.90Å     R-factor:   0.164     R-free:   0.200
Authors: A.A.Armstrong,V.Lafont,Y.Kiso,E.Freire,L.M.Amzel
Key ref: V.Lafont et al. (2007). Compensating enthalpic and entropic changes hinder binding affinity optimization. Chem Biol Drug Des, 69, 413-422. PubMed id: 17581235
Date:
17-Apr-07     Release date:   08-May-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Q9J2P7  (Q9J2P7_HV1) -  Protease (Fragment) from Human immunodeficiency virus type 1
Seq:
Struc: 		99 a.a.
99 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 

 
Chem Biol Drug Des 69:413-422 (2007)
PubMed id: 17581235  
 
 
Compensating enthalpic and entropic changes hinder binding affinity optimization.
V.Lafont, A.A.Armstrong, H.Ohtaka, Y.Kiso, L.Mario Amzel, E.Freire.
 
  ABSTRACT  
 
A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21371789 F.Daidone, R.Florio, S.Rinaldo, R.Contestabile, M.L.di Salvo, F.Cutruzzolà, F.Bossa, and A.Paiardini (2011).
In silico and in vitro validation of serine hydroxymethyltransferase as a chemotherapeutic target of the antifolate drug pemetrexed.
  Eur J Med Chem, 46, 1616-1621.  
21472180 F.G.Sun, and S.Ye (2011).
N-heterocyclic carbene-catalyzed [4 + 1] annulation of phthalaldehyde and imines.
  Org Biomol Chem, 9, 3632-3635.  
21421319 G.Tresadern, J.M.Bartolome, G.J.Macdonald, and X.Langlois (2011).
Molecular properties affecting fast dissociation from the D2 receptor.
  Bioorg Med Chem, 19, 2231-2241.  
21199371 J.A.Worrall, and J.M.Mason (2011).
Thermodynamic analysis of Jun-Fos coiled coil peptide antagonists.
  FEBS J, 278, 663-672.  
19906645 A.Palencia, A.Camara-Artigas, M.T.Pisabarro, J.C.Martinez, and I.Luque (2010).
Role of interfacial water molecules in proline-rich ligand recognition by the Src homology 3 domain of Abl.
  J Biol Chem, 285, 2823-2833.
PDB codes: 3eg0 3eg1 3eg2 3eg3 3egu
19875447 H.Qin, R.Noberini, X.Huan, J.Shi, E.B.Pasquale, and J.Song (2010).
Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity.
  J Biol Chem, 285, 644-654.
PDB code: 3gxu
19960014 J.E.Ladbury, G.Klebe, and E.Freire (2010).
Adding calorimetric data to decision making in lead discovery: a hot tip.
  Nat Rev Drug Discov, 9, 23-27.  
20028396 Y.Kawasaki, E.E.Chufan, V.Lafont, K.Hidaka, Y.Kiso, L.Mario Amzel, and E.Freire (2010).
How much binding affinity can be gained by filling a cavity?
  Chem Biol Drug Des, 75, 143-151.
PDB codes: 3kdb 3kdc 3kdd
  20862304 Y.Liu, L.M.Gierasch, and I.Bahar (2010).
Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs.
  PLoS Comput Biol, 6, 0.  
19425594 A.A.Edwards, J.M.Mason, K.Clinch, P.C.Tyler, G.B.Evans, and V.L.Schramm (2009).
Altered enthalpy-entropy compensation in picomolar transition state analogues of human purine nucleoside phosphorylase.
  Biochemistry, 48, 5226-5238.  
19882701 A.D.Scott, C.Phillips, A.Alex, M.Flocco, A.Bent, A.Randall, R.O'Brien, L.Damian, and L.H.Jones (2009).
Thermodynamic Optimisation in Drug Discovery: A Case Study using Carbonic Anhydrase Inhibitors.
  ChemMedChem, 4, 1985-1989.
PDB codes: 2weg 2weh 2wej 2weo
19793186 E.Freire (2009).
A thermodynamic approach to the affinity optimization of drug candidates.
  Chem Biol Drug Des, 74, 468-472.  
18335423 D.G.Udugamasooriya, and M.R.Spaller (2008).
Conformational constraint in protein ligand design and the inconsistency of binding entropy.
  Biopolymers, 89, 653-667.  
18703160 E.Freire (2008).
Do enthalpy and entropy distinguish first in class from best in class?
  Drug Discov Today, 13, 869-874.  
18826206 H.A.Carlson, R.D.Smith, N.A.Khazanov, P.D.Kirchhoff, J.B.Dunbar, and M.L.Benson (2008).
Differences between high- and low-affinity complexes of enzymes and nonenzymes.
  J Med Chem, 51, 6432-6441.  
18763714 J.T.Nguyen, Y.Hamada, T.Kimura, and Y.Kiso (2008).
Design of potent aspartic protease inhibitors to treat various diseases.
  Arch Pharm (Weinheim), 341, 523-535.  
18482338 L.Li, J.J.Dantzer, J.Nowacki, B.J.O'Callaghan, and S.O.Meroueh (2008).
PDBcal: a comprehensive dataset for receptor-ligand interactions with three-dimensional structures and binding thermodynamics from isothermal titration calorimetry.
  Chem Biol Drug Des, 71, 529-532.  
18189414 T.Dasgupta, and K.S.Anderson (2008).
Probing the role of parasite-specific, distant structural regions on communication and catalysis in the bifunctional thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum.
  Biochemistry, 47, 1336-1345.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

spacer
spacer