Coevolution and subsite decomposition for the design of resistance-evadingHIV-1 protease inhibitors

Drug resistance sharply limits the effectiveness of human immunodeficiency virus (HIV) protease inhibitors in acquired immunodeficiency syndrome thera py. In previous work, we presented methods for design of resistance-evading inhibitors using a computational coevolution technique. Here, we report su bsite decomposition experiments that examine the relative importance and ro les of each subsite in HIV protease, and the constraints on robust inhibito r design that are imposed by possible resistance mutations in each subsite. The results identify several structural features of robust resistance-evad ing inhibitors for use in drug design, and show their basis int he constrai nts imposed by the range of allowable mutation in the protease. In particul ar, the results identify the P3 and P3' sites as being particularly sensiti ve to protease mutation: inhibitors designed to fill the S3 and S3' sites o f the wild-type protease will be susceptible to viral resistance, but inhib itors with side-chains smaller than a phenylalanine residue at P3 and P3', preferably medium-sized amino acids in the range from valine to leucine and isoleucine residues, will be more robust in the face of protease resistanc e mutation. (C) 1999 Academic Press.