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D S Goodsell

Publications and source records attributed to D S Goodsell.

At least 37 records · Page 2Linked to original sources
PubMed1999

Coevolution and subsite decomposition for the design of resistance-evading HIV-1 protease inhibitors.

Drug resistance sharply limits the effectiveness of human immunodeficiency virus (HIV) protease inhibitors in acquired immunodeficiency syndrome therapy. In previous work, we presented methods for design of resistance-evading inhibitors using a computational coevolution technique. Here, we report subsite decomposition experiments that examine the relative importance and roles of each subsite in HIV protease, and the constraints on robust inhibitor design that are imposed by possible resistance mutations in each subsite. The results identify several structural features of robust resistance-evading inhibitors for use in drug design, and show their basis in the constraints imposed by the range of allowable mutation in the protease. In particular, the results identify the P3 and P3' sites as being particularly sensitive to protease mutation: inhibitors designed to fill the S3 and S3' sites of the wild-type protease will be susceptible to viral resistance, but inhibitors 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 resistance mutation.

Computational Biology↗
PubMed1999

Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.

We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain the ability to bind and cleave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possible.

Amino Acid Sequence↗
PubMed1999

Docking of 4-oxalocrotonate tautomerase substrates: implications for the catalytic mechanism.

The enzyme 4-oxalocrotonate tautomerase catalyzes the ketonization of dienols, which after further processing become intermediates in the Krebs cycle. The enzyme uses a general acid-base mechanism for proton transfer: the amino-terminal proline has been shown to function as the catalytic base and Arg39 has been implicated as the catalytic acid. We report the results of molecular docking simulations of 4-oxalocrotonate tautomerase with two substrates, 2-hydroxymuconate and 5-carboxymethyl-2-hydroxymuconate. pKa calculations are also performed for the free enzyme. The predicted binding mode of 2-hydroxymuconate is in agreement with experimental data. A model for the binding mode of 5-carboxymethyl-2-hydroxymuconate is proposed which explains the lower catalytic efficiency of the enzyme toward this substrate. The pKa predictions and docking simulations support residue Arg39 as the general acid for the enzyme catalysis.

Aldehydes↗