Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1.

Eliane Briand,Olivier Taboureau,Kristian Linnet,Ragnar Thomsen,Henrik Berg Rasmussen,Søren Brunak

doi:10.3390/molecules24152747

Abstract

The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning approaches improves the prediction of CES1 inhibitors compared to a docking study using only one crystal structure.

Highlights

The incidence of drug failures remains high in late-stage clinical development phases, leading to a key challenge in drug discovery [1]
Drug response is a complex phenotype depending on numerous genetic environmental and behavioral factors, studies have demonstrated that pharmacokinetics, and notably metabolism, can alter the response to medicine and lead to increased risk of adverse drug reactions (ADRs) through for example unanticipated drug–drug interactions (DDIs) [3]
The active site is located at the base of a 10–15 Å deep catalytic gorge located at the interface of the three domains and is predominantly lined by hydrophobic residues

Summary

Introduction

The incidence of drug failures remains high in late-stage clinical development phases, leading to a key challenge in drug discovery [1]. CES1 is implicated in the hydrolysis of many drugs (and prodrugs), transforming an ester, amide or carbamate moiety into its respective free acids, amines or alcohols [7]. It metabolizes structurally diverse compounds such as the psychostimulant methylphenidate (MPH) [8] used in the treatment of hyperkinetic disorders, commonly prescribed angiotensin-converting enzyme (ACE) inhibitors (enalapril, trandolapril, ramipril, quinapril, imidapril) [9], the anti-cancer agent (CPT-11) [10,11], the anti-influenza prodrug oseltamivir [12], and several narcotics and analgesics (cocaine, meperidine) [13,14]. In addition to xenobiotic substrates, CES1 is involved in the processing of several endogenous compounds such as fatty acids and cholesterol derivatives [15,16]

Methods

Results

Discussion

Conclusion