3KDB

Crystal Structure of HIV-1 Protease (Q7K, L33I, L63I) in Complex with KNI-10006

Summary for 3KDB

• Entry DOI: 10.2210/pdb3kdb/pdb
• Related: 2PK5 2PK6 3KDC 3KDD
• Related PRD ID: PRD_000575
• Descriptor: Protease, GLYCEROL, (4R)-3-[(2S,3S)-3-{[(2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-4-phenylbutanoyl]-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, ... (4 entities in total)
• Functional Keywords: viral protein, hydrolase, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• Total number of polymer chains: 2
• Total formula weight: 22333.49

Authors

Chufan, E.E.,Lafont, V.,Freire, E.,Amzel, L.M. (deposition date: 2009-10-22, release date: 2010-03-02, Last modification date: 2023-09-06)

Primary citation

Kawasaki, Y.,Chufan, E.E.,Lafont, V.,Hidaka, K.,Kiso, Y.,Mario Amzel, L.,Freire, E.
How much binding affinity can be gained by filling a cavity?
Chem.Biol.Drug Des., 75:143-151, 2010

PubMed Abstract: Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl, and CH(3)) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to -1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5-fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25-fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself [CH(CH(3))(2)]. It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.

PubMed: 20028396
DOI: 10.1111/j.1747-0285.2009.00921.x

Experimental method

X-RAY DIFFRACTION (1.66 Å)