An in silico pipeline for the discovery of multitarget ligands: A case study for epi-polypharmacology based on DNMT1/HDAC2 inhibition.

The search for novel therapeutic compounds remains an overwhelming task owing to the time-consuming and expensive nature of the drug development process and low success rates. Traditional methodologies that rely on the one drug-one target paradigm have proven insufficient for the treatment of multifactorial diseases, leading to a shift to multitarget approaches. In this emerging paradigm, molecules with off-target and promiscuous interactions may result in preferred therapies. In this study, we developed a general pipeline combining machine learning algorithms and a deep generator network to train a dual inhibitor classifier capable of identifying putative pharmacophoric traits. As a case study, we focused on dual inhibitors targeting DNA methyltransferase 1 (DNMT) and histone deacetylase 2 (HDAC2), two enzymes that play a central role in epigenetic regulation. We used this approach to identify dual inhibitors from a novel large natural product database in the public domain. We used docking and atomistic simulations as complementary approaches to establish the ligand-interaction profiles between the best hits and DNMT1/HDAC2. By using the combined ligand- and structure-based approaches, we discovered two promising novel scaffolds that can be used to simultaneously target both DNMT1 and HDAC2. We conclude that the flexibility and adaptability of the proposed pipeline has predictive capabilities of similar or derivative methods and is readily applicable to the discovery of small molecules targeting many other therapeutically relevant proteins.