Abstract
When excessively activated, C1 is insufficiently regulated, which results in tissue damage. Such tissue damage causes the complement system to become further activated to remove the resulting tissue damage, and a vicious cycle of activation/tissue damage occurs. Current Food and Drug Administration approved treatments include supplemental recombinant C1 inhibitor, but these are extremely costly and a more economical solution is desired. In our work, we have utilized an existing data set of 136 compounds that have been previously tested for activity against C1. Using these compounds and the activity data, we have created models using principal component analysis, genetic algorithm, and support vector machine approaches to characterize activity. The models were then utilized to virtually screen the 72 million compound PubChem repository. This first round of virtual high-throughput screening identified many economical and promising inhibitor candidates, a subset of which was tested to validate their biological activity. These results were used to retrain the models and rescreen PubChem in a second round vHTS. Hit rates for the first round vHTS were 57%, while hit rates for the second round vHTS were 50%. Additional structure–property analysis was performed on the active and inactive compounds to identify interesting scaffolds for further investigation.
Highlights
Complement factor C1s (EC 3.4.21.42) is a subcomponent of the C1 complex in the complement system of the innate portion of the immune system [1]
The pan-assay interference compounds (PAINS)-free training set yielded a total of 1072 atomic Signatures of heights 0, 1, and 2
The filtered atomic Signatures are used by genetic algorithm (GA)-support vector machine (SVM) to build models
Summary
Complement factor C1s (EC 3.4.21.42) is a subcomponent of the C1 complex in the complement system of the innate portion of the immune system [1]. The complex circulates the body at a concentration, relative to serum, of 0.17 μM [1] and is mainly produced and/or assembled in monocytes and macrophages [2,3]. The complement factor 1 gene for the entire complex is found on the fourth chromosome [5] and encodes for a 750 kDa pentameric glycoprotein comprised of three subcomponent proteins: one C1q, two C1r, and two C1s [1]. C1q is the pattern recognition subunit and binds to a wide variety of targets [6]. C1q recognition and binding cleaves and activates C1r, which, in turn, cleaves and activates C1s [7].
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