In silica modelling

Norinder U. In silica modelling of ADMET—a minireview of work from 2000 to 2004. SAR QSAR Environ Res 2005 16 1-11. 

Figure 20.1 In silica modeling targets of drug disposition.

The study of DMPK has changed from a descriptive to a much more predictive science [3]. This is driven by great progress in bioanalytics, development of in vitro assays and in silica modeling/simulation, and a much better basic understanding of the processes. Thus, and fortunately, ADME-related attrition has lowered from around 40% in 1990 to around 10% in 2005 [13]. 

The experimental Pjpp data have been used to build predictive models. However, since PAMPA is already a model, an in silica model based on this is a model of a model. The predictability for in vivo permeability or absorption of such in silica PAMPA model can be queshoned (see Eq. 11), since it is two steps from reality ... 

Van de Waterbeemd, H., Gifford, E. ADMET in silica modeling towards in... 

Aronov, A. M. Predictive in silica modeling for hERG channel blockers. Drug Discov. Today 2005, 10,149-155. 

Galland, A. Towards the validation of in silica models and physicochemical filters to identify and characterize new chemical entities, PhD Thesis, University of Lausanne, 2004. 

Pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. Hence, physicochemical as well as ADMET properties need to be fine-tuned even in the lead optimization phase. Recently developed in silica approaches will further increase model predictivity in this area to improve compound design and to focus on the most promising compounds only. A recent overview on ADME in silica models is given in Ref [128]. 

Several in silica models for prediction of oral absorption are available [133-136]. Simple models are based on only few descriptors like logP, logD, or polar surface area (PSA), while they are only applicable if the compounds are passively absorbed. In case of absorption via active transporters or if efflux is involved, prediction of absorption is still not successful. 

The approach discussed to use VolSurf derived in silica models to understand structure-PK relationships for pharmacokinetic properties was also applied to one series of selective cardiac KATP channel blockers [160]. It was found that compounds fulfilling the predefined selectivity profile exhibit only less-optimal pharmacokinetic properties because of a short plasma mean residential time (MRT). Consequently, the MRT for 28 compounds from rabbit iv studies for one series was used as dependent variable to derive a VolSurf PLS model in addition to ligand affinity SAR data. The chemical... 

Classically the term in silica modeling referred to the process of building a model to predict a given endpoint from a set of molecular properties derived purely from the chemical structure of a number of compounds of which the endpoint of interest is known. 

Unfortunately the number of in silica modeling studies on brain membrane permeability is significantly smaller than for human intestinal absorption, resulting in a lack of consensus about how to assess brain penetration (both in vitro and in vivo) and the intrinsic difficulty of measuring this particular endpoint, which overall results in a low turnover of data generation that could be used to build in silica models [95, 96]. For this reason, the in silica models used to assess brain permeability in the discovery process focus normally on P-gp efflux and some measure of in vitro membrane permeability, methods which are reviewed in the next section. 

One of the main in vitro permeability assays used in the pharmaceutical industry has been for many years the Caco-2 monolayer. Therefore, most of the in silica models developed to predict permeability were based on Caco-2 data. Hou and Johnson produced a couple of reviews that comprehensibly summarizes the recent efforts using Caco-2 permeability data [92, 94]. All those models are designed to predict the influx or apparent permeability of drugs in the same direction as intestinal absorption occurs, that is, from the apical to the basal side of the cell line, regardless of the extent of active transport involved in the permeation process. 

As the current trends show, the in silica modeling of membrane permeability is evolving towards a better integration of the contemporary understanding of absorption pathways in the predictive systems [112]. If the hit-to-lead in silica profiling process wants to succeed in the prediction of in viva absorption, in silica modeling needs to expand in the following three directions ... 

And finally, whilst this chapter focuses on CYP enzymes, the same principles can be applied to any enzyme or transporter providing the tools to do the job are available (e.g., in silica models, specific substrates/inhibitors, recombinant systems). 

When building in silica models for biopharmaceutical properties, one must understand the molecular nature of the property in order to select molecular descriptors that have relevance to the problem. Plasma protein binding involves the reversible... 

ADMFT in silica modelling towards prediction paradise Nature Reviews. Drug Discovery, 2, 192-204. 

Permeability, predicted by in silica models, is high for certain conjugates, i.e., phenol and benzyl alcohol glucoside conjugates. 

Miners JO, Smith PA, Sorich MJ, McKinnon RA, Mackenzie PL Predicting human drug glucuronidation parameters application of in vitro and in silica modeling approaches. Annu Rev Pharmacol Toxicol 2004 44 1-25. 

Cheng A, Dixon SL (2003) In silica models for the prediction of dose-dependent human hepatotoxicity. J Comput Aided Mol Des 17, 811-23. 

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