Here we report a new drug design workflow that facilitates the transfer of structure-activity relationships (SARs) and recommends alternative fragments from SAR databases. We first prepare two collections of matched molecular series (MMS) comprising a query set of compounds with their SARs and a set derived from reference SAR databases. The second step detects MMS from the reference SAR sources, which identifies profiles similar to a query MMS according to integrated similarities of scaffold shapes and SAR trends. The third step enumerates new compounds with improved activity profiles compared with a query compound computed using a collaborative filtering algorithm. Our workflow detected direct and latent relationships between a query MMS and those derived from the reference SAR sources. Retrospective application of this workflow to the identification of factor Xa inhibitors yielded recommendations with higher predictive accuracy than a conventional quantitative SAR technique. Moreover, potent S1 binding elements were identified using SAR knowledge independent of information about ligand-protein complexes.
Trifluorothymidine (TFT) has antitumor activity, but it is easily metabolized to inert trifluorothymine by thymidine phosphorylase (TP). Accordingly, TFT alone cannot show satisfactory clinical antitumor effects. Human TP (HTP) is the main enzyme of pyrimidine nucleoside phosphorylase in human. Therefore, it has been necessary to develop a HTP inhibitor to maintain antitumor activity of TFT. Here we reveal the drug design process of HTP inhibitor based on SBDD and classical QSAR analysis. Thymine was selected as a seed compound and then 5-chlorouracil (3) was selected as a lead compound. The introduction of the imino moiety to C6 position of the lead compound (3) enhanced the inhibitory activity of TP. As a result, 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI) was chosen as the candidate for the clinical trials. And TAS-102 (the combination of TFT and TPI in a 1:0.5 molar ratio) has been approved as Trifluridine/Tipiracil (Lonsurf) for the treatment of metastatic colorectal cancer in Japan, United States and EU.
Pseudohypoaldosteronism type II has been known as a rare autosomal dominant disorder caused by WNK1 [with no K (lysine) protein kinase-1] or WNK4. These serine/threonine kinases have unusual structures with a back pocket located just behind the ATP binding site. Moreover, a lysine residue (Lys 233 in WNK1) in a glycine-rich loop plays a key role in their activity. In this work, we performed docking simulations of about 9,000 compounds from a fragment library with the back pocket of WNK1 in order to discover candidate lead compounds for development of specific inhibitors. Based on binding energy index, we selected β-tetralone (compound 5) as a lead structure that interacts with the back pocket, but not with the hinge region of WNK1. Guided by the four predicted docking patterns of β-tetralone with the back pocket, we designed four derivatives A-D that were expected to form hydrogen bonds with Lys 233. Docking studies indicated that these derivatives interact selectively with Lys 233, but not with the hinge region. These compounds are considered potential lead compounds for developing selective WNK inhibitors.