# A Comprehensive In Vitro and In Silico Approach for Targeting 4-Hydroxyphenyl Pyruvate Dioxygenase: Towards New Therapeutics for Alkaptonuria

## TL;DR

This study explores new drug candidates for treating Alkaptonuria by targeting a specific enzyme using a combination of lab and computer-based methods.

## Contribution

The paper introduces an integrated in vitro and in silico approach to evaluate 4-HPPD inhibitors for Alkaptonuria treatment.

## Key findings

- Triketone compounds were assessed for their inhibitory efficacy and residence time on 4-HPPD.
- The study identified pharmacokinetic and pharmacodynamic properties of novel 4-HPPD inhibitors.
- The findings provide a foundation for developing safer and more effective Alkaptonuria treatments.

## Abstract

Alkaptonuria (AKU) is an ultra-rare genetic disorder caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene, leading to the accumulation of homogentisic acid (HGA). Current treatment options are limited, with Nitisinone (Orfadin or NTBC) being the only approved drug. However, its long-term use raises concerns due to significant adverse effects, highlighting the urgent need for safer alternatives. AKU manifests with progressive and often painful symptoms, severely impacting patients’ quality of life. Identifying new therapeutic approaches to inhibit 4-hydroxyphenyl pyruvate dioxygenase (4-HPPD) is critical to improving outcomes for AKU patients. In this study, we present a novel integrated in vitro and in silico strategy to assess the residence time of 4-HPPD inhibitors. In particular, we evaluated several features of a set of triketone compounds including their inhibitory efficacy, residence time, and ochronotic pigment accumulation. By means of our integrated approach, we investigated the pharmacokinetic and pharmacodynamics properties of novel 4-HPPD inhibitors and provided a promising foundation for the development of safer and more effective treatments for AKU.