Pharma Algorithms
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Pharma Algorithms. www.ap-algorithms.com. Classification Analysis (C-SAR) in Predicting Pgp Substrate Specificity. R. Didziapetris, P. Japertas, A. Petrauskas. Pharma Algorithms. Classification SAR. ►. Based on recursive partitioning Groups compounds into classes

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Slide1 l.jpg

Pharma Algorithms

www.ap-algorithms.com

Classification Analysis (C-SAR) in

Predicting Pgp Substrate Specificity

R. Didziapetris, P. Japertas, A. Petrauskas


Classification sar l.jpg

Pharma Algorithms

Classification SAR

Based on recursive partitioning

Groups compounds into classes

Aims at differentiating biol. mechanisms


Recursive partitioning l.jpg

Pharma Algorithms

Recursive Partitioning

A multistep procedure

At each step, finds the best descriptor with the best cut-off value

Single-click conversion into decision tree

MV > 300

Acid pKa > 5


P gp data l.jpg

Pharma Algorithms

P-gp Data

850 compounds compiled: 322 substrates + 528 non-substrates

“Two-class” model used: 1 – substrates, 0 – non-substrates

P-gp substrate specificity analyzed, not inhibition, and not induction

Loperamide -1

Tamoxifen - 0


Physchem requirements for non substrates l.jpg

Pharma Algorithms

PhysChem Requirements for Non-substrates

Negative

charge

Increases

MV cut-off

Decreases

specificity

Positive

charge

Decreases

MV cut-off

More data required


Physchem requirements for substrates l.jpg

Pharma Algorithms

PhysChem Requirements for Substrates

1.

No acid group with pKa < 5

3.

Ertl’s tPSA > 72 A2, log P > 0.58, Abraham's beta >1.8, alpha = 0.5 - 3.3

2.

MV = 534 to 674 cm3/mol(MW = c.a. 700 to 900)

Examples

True: 50False: 3


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Pharma Algorithms

Structural Factors

Two types of “biophores”:

“Mechanistic”

“Statistical”

Depend on biological class of compounds

Do not depend on biological class of compounds

Lead to the “knowledge- based” filters

Lead to the “statistical induction” algorithms


Examples of mechanistic biophores l.jpg

Pharma Algorithms

Examples of “Mechanistic Biophores”

Similar skeletons were also identified for anthracyclines, talinolol, quinidine and etoposide groups.


Examples of statistical biophores l.jpg

Pharma Algorithms

Examples of “Statistical Biophores”

The good statistical significance + interchangeability of biophores

Seelig-type non-specific fragments - many alternative biophores produce equally good results


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Pharma Algorithms

Conclusions

“Knowledge” approach is preferable, but more data is needed.

“Statistical” approach produces higher % of false predictions.

Two approaches can be used together.


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