Inhibitor design by wrapping packing defects in HIV-1 proteins.
Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named "dehydrons," are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block protein-protein associations is also discussed.
Fernández
Ariel
A
School of Informatics and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 714 North Senate Avenue, Indianapolis, IN 46202, USA. ariel@uchicago.edu
Rogale
Kristina
K
Scott
Ridgway
R
Scheraga
Harold A
HA
D020134:Catalytic Domain; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D012191:Retroviridae Proteins / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014867:Water
D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D012191:Retroviridae Proteins; D014867:Water; D019427:HIV Integrase; D016333:HIV Protease