Research & Innovation
Publications
Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes
PMU Author
Peter Goettig
All Authors
Peter Goettig, Xingchen Chen, Jonathan M Harris
Journal association
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Abstract
Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy Delta G with the YASARA plugin FoldX were used to derive inhibition constants Ki from PDB coordinates of protease-inhibitor complexes. At the same time, corresponding KD values were obtained from the PRODIGY server. These results correlated well with the experimental values, particularly for serine proteases. In addition, analyses were performed for inhibitory complexes of cysteine and aspartic proteases, as well as of metalloproteases, whereby the PRODIGY data appeared to be more consistent. Based on our analyses, we calculated theoretical Ki values for trypsin with sunflower trypsin inhibitor (SFTI-1) variants, which yielded the more rigid Pro14 variant, with probably higher potency than the wild-type inhibitor. Moreover, a hirudin variant with an Arg1 and Trp3 is a promising basis for novel thrombin inhibitors with high potency. Further examples from antibody interaction and a cancer-related effector-receptor system demonstrate that our approach is applicable to protein interaction studies beyond the protease field.
Keywords
Serine Endopeptidases, Trypsin Inhibitors/pharmacology, Trypsin/metabolism, Helianthus/metabolism, Peptide Hydrolases, Protease Inhibitors/pharmacology