Identification of FDA‐approved Drugs that Computationally Bind to MDM2

Abstract

The integrity of the p53 tumor suppressor pathway is compromised in the majority of cancers. In 7% of cancers, p53 is inactivated by abnormally high levels of MDM2—an E3 ubiquitin ligase that polyubiquitinates p53, marking it for degradation. MDM2 engages p53 through its hydrophobic cleft and blockage of that cleft by small molecules can re-establish p53 activity. Small molecule MDM2 inhibitors have been developed, but there is likely to be a high cost and long time period before effective drugs reach the market. An alternative is to repurpose FDA-approved drugs. This report describes a new approach, called Computational Conformer Selection, to screen for compounds that potentially inhibit MDM2. This screen was used to computationally generate up to 600 conformers of 3,244 FDA-approved drugs. Drug conformer similarities to 41 computationally-generated conformers of MDM2 inhibitor nutlin 3a were ranked by shape and charge distribution. Quantification of similarities by Tanimoto combo scoring resulted in scores that ranged from 0.142 to 0.802. In silico docking of drugs to MDM2 was used to calculate binding energies and to visualize contacts between the top-ranking drugs and the MDM2 hydrophobic cleft. We present 15 FDA-approved drugs predicted to inhibit p53/MDM2 interaction.

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

“…22 Since the submission of this manuscript a crystal structure of TASK-1, bound to inhibitory compounds, was released. Consistent with previously published work, 20,22,40,41 L122 and L239, along with some other amino acids, were important for binding and trapping of these inhibitory compounds, within TASK-1 channels. For two novel inhibitory compounds (BAY 1000493 and BAY 2341237) it was shown that the compounds bind within an inner vestibule, directly below the selectivity filter.…”

“…By truncating the channel, it is possible that the channel has been pushed into an open state, perhaps by locking the channel into a particular phosphorylation state, or because gating at the selectivity filter is disrupted by C-terminus truncation. 22 This correlates with another previous molecular modelling study of doxapram, which suggests the drug has a high affinity for a hydrophobic cleft in which to bind 40 and with a study conducted on TASK-3_L122D, which suggested that mutating this amino acid to an aspartate produces a fixed open conformation that reduces the effects of anaesthetics. 37,38 Surprisingly, however, truncation of murTASK-3 channels, resulted in a significant reduction in current recorded through these channels, but this still attenuated the effect of doxapram.…”

RepurposeVS: A Drug Repurposing-Focused Computational Method for Accurate Drug-Target Signature Predictions

“…Many efforts for computationally predicting drug-target interactions exist, spanning both chemo-centric [7, 8] and target-based methodologies [9, 10]. Chemo-centric approaches utilize physical and chemical information obtained from ligands.…”

“…Chemo-centric approaches utilize physical and chemical information obtained from ligands. Some approaches relate receptors based on the chemical similarity [7] as well as shape similarity [8] between ligands. Large public databases that aid in extracting ligand-based data for informatics also exist [9].…”

Discovery of Novel Isatin-Based p53 Inducers

“…The p53-binding part of MDM2 is rigid, and its solved structure is widely used in molecular docking studies. 13 Most of the MDM2 inhibitors mimic the structure of the TAD1 α-helix 14 and hence form the same intermolecular contacts with the hydrophobic MDM2 pocket as the original p53. An alternative concept of stapled peptides was shown to be a successful strategy in attempts to inhibit MDM2.…”