In Silico Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK): Utility and Best Practices. An Industry Perspective from the International Consortium for Innovation through Quality in Pharmaceutical Development

Abstract

In silico tools to investigate absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK) properties of new chemical entities are an integral part of the current industrial drug discovery paradigm. While many companies are active in the field, scientists engaged in this area do not necessarily share the same background and have limited resources when seeking guidance on how to initiate and maintain an in silico ADME-PK infrastructure in an industrial setting. This work summarizes the views of a group of industrial in silico and experimental ADME scientists, participating in the In Silico ADME Working Group, a subgroup of the International Consortium for Innovation through Quality in Pharmaceutical Development (IQ) Drug Metabolism Leadership Group. This overview on the benefits, caveats, and impact of in silico ADME-PK should serve as a resource for medicinal chemists, computational chemists, and DMPK scientists working in drug design to increase their knowledge in the area.

Pronounced activity of aromatic selenocyanates against multidrug resistant ESKAPE bacteria

“…Thirteen arylmethyl selenocyanates (1-13, Figure 1) were designed and synthesized based on basic pharmacokinetic and pharmacodynamic considerations. [42][43][44] The compounds were produced employing appropriate commercially available arylmethyl halides and potassium selenocyanate (KSeCN), according to the general procedure described by Wheeler and Merriam, and with minor modifications (Figure 1). All of the compounds -of which four are novel -were obtained in good yields (62- Crystallographic Studies.…”

New Di(heteroaryl)ethenes as Apoptotic Anti‐proliferative Agents Towards Breast Cancer: Design, One‐Pot Synthesis and In Vitro Evaluation

“…In order to search for novel drug candidates able to overcome these challenges, their pharmacokinetic behaviour should be carefully assessed in terms of potency, selectivity, oral bioavailability (for orally administered drugs), therapeutic efficacy, along with an acceptable side effects profile. It is worth noting that the evaluation of the absorption, distribution, metabolism, and excretion (ADME) profiles accounts for most of the high cost and the time taken to bring a new compound to market …”

Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence?

“…The hope for broad scale models has been challenged by the shear size of accessible medicinal chemistry space [40]. Over the last two decades, three themes have been clear: the development of large scale QSAR models, the attempt to extract "simple rule models" for complex properties and the development of matched molecular pair analysis (MMPA) to analyze success frequencies for biological or physical properties [41].…”