In silico modeling

The reliability of the in silico models will be improved and their scope for predictions will be broader as soon as more reliable experimental data are available. However, there is the paradox of predictivity versus diversity. The greater the chemical diversity in a data set, the more difficult is the establishment of a predictive structure-activity relationship. Otherwise, a model developed based on compounds representing only a small subspace of the chemical space has no predictivity for compounds beyond its boundaries. 

Defranoux NA, Stokes CL, Young DL, Kahn AJ. In silico modeling and simulation of bone biology a proposal. / Bone Miner Res 2005 20 1079-84. 

Van de Waterbeemd H, Gifford E. ADMET in silico modelling towards prediction paradise Nat Rev Drug Discov 2003 2 192-204. 

As discussed above, all ADMET aspects are dependent on each other and should all be considered when making predictions. Integrated analysis of different aspects of drug pharmacokinetic profiles is yet another future trend. Ultimately, drug ADMET properties should be predicted based on an integration of a compilation of in silico models reflecting different aspects of the process. 

Pardridge WM, Log(BB). PS products and in silico models of drug brain penetration. Drug Discov Today 2004 9 392-3. 

Price ND, Papin JA, Schilling CH, Palsson BO. Genome-scale microbial in silico models the constraints-based approach. Trends Biotechnol 2003 21 162-9. 

Virtual organs will increasingly determine bio-medical research. Advantages of in silico models include the following ... 

While the first three points improve the quantity and quality of information, in silico models benefit further from their unrestricted potential for customised presentation of results. This allows addressing aspects like individual preferences in information gathering, remote usage of models, interactive teaching and training, etc. 

Thus, in silico models are by no means self-sufficient. They are irreplaceable for the future progress of bio-medicine. They do not aim, however, to substitute but to improve bio-medical research, which will remain indispensable, not the least for model development and validation. 

In silico models will aid both the standardisation and individualisation of medical care. Standardisation of diagnoses, drug and device descriptions, procedures, etc. will make relevant information more readily and more widely available. On the other hand, advanced models will allow development of patient-specific procedures for diagnosis and treatment. This will move the focus from the treatment of diseases to the curing of patients. 

Hewitt M et al. (2007) Structure-based modelling in reproductive toxicology (Q)SARs for the placental barrier. SAR QSAR Environ Res 18(l-2) 57-76 Mekenyan O et al. (2003) In silico modelling of hazard endpoints current problems and perspectives. SAR QSAR Environ Res 14(5-6) 361-371... 

Benfenati E (2010) The CAESAR project for in silico models for the REACH legislation. Chem Cent J 4 11... 

Finally, a QSAR evaluation of different chemicals from waste-related products and recycling is shown in order to underline how in silico models can be used as a valid tool to fill in the gaps and to obtain information on toxicological profile and physicochemical information on compounds. In particular, a focus on compounds suggested by EU project Riskcycle is presented. 

In recent years, the scientific community has focused on the need to develop alternative methods to animal experiments, including cell-based in vitro methods and in silico models, based on statistics and informatics. 

Fig. 5.2. Two-step process for evaluation of intestinal drug absorption. The first step represents the prediction of intestinal permeability (e.g., over Caco-2 monolayers) from in-silico models or from physico-chemical...

The aim of the present example was to investigate whether the assessment of an in silico model of metabolic stability from a training set of several hundred drugs or drug-like compounds in human CYP3A4 cDNA-expressed microsomal preparations, would offer a suitable approach to predict the metabolic stability of external compounds. 

In silico Models for Estimating Human Oral Bioavailability... 

Fig. 19.5. In silico model for estimating oral bioavailability. Plot of predicted versus observed bioavailability in humans for 591 drugs [22],...

Finally, one of the main limitations of this model is the large false-positive rate and large experimental errors. Indeed, the primary limitation of the QSAR and in silico models is the high false-positive rates in oral bioavailability predictions. 

Generating valid in silico models requires high quality databases for model training. True values of VD in human require that the parameters are calculated from pharmacokinetic data measured after intravenous administration. From equation 7 above, calculation of VDSS requires that the dose that enters the bloodstream is known, which can only be guaranteed by intravenous... 

Aronov, A.M. (2005) Predictive in silico modeling for hERG channel blockers. Drug Discovery Today, 10, 149-155. 

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