In silico ADME/tox comes of age: twenty years later

Abstract

1. In the early 2000s pharmaceutical drug discovery was beginning to use computational approaches for absorption, distribution, metabolism, excretion and toxicity (ADME/Tox, also known as ADMET) prediction. This emphasis on prediction was an effort to reduce the risk of later stage failures from ADME/Tox.

2. Much has been written in the intervening twenty plus years and significant expenditure has occurred in companies developing these in silico capabilities which can be gleaned from publications. It is therefore an appropriate time to briefly reflect on what was proposed then and what the reality is today.

3. 20 years ago, we tended to optimise bioactivity and perhaps one ADME/Tox property at a time. Previously pharmaceutical companies needed a whole infrastructure for models – in silico and in vitro experts, IT, champions on a project team, educators and management support. Now we are in the age of generative de novo design where bioactivity and many ADME/Tox properties can be optimised and large language model technologies are available.

4. There are also some challenges such as the focus on very large molecules which may be outside of current ADME/Tox models.

5. We provide an opportunity to look forward with the increasing public data for ADME/Tox as well as expanded types of algorithms available.

Keywords:

• ADME/Tox
• in silico
• de novo

Acknowledgements

SE kindly acknowledges the many collaborators on in silico ADME/Tox with whom he has been fortunate to work with over the past 20+ years.

Disclosure statement

S.E. is owner, all others are employees of Collaborations Pharmaceuticals, Inc.

Additional information

Funding

We kindly acknowledge NIH funding: 2R44GM122196-04A1 from NIGMS and 2R44ES031038-02A1 from NIEHS.