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Pharma Algorithms

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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Pharma Algorithms

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  1. Pharma Algorithms www.ap-algorithms.com Classification Analysis (C-SAR) in Predicting Pgp Substrate Specificity R. Didziapetris, P. Japertas, A. Petrauskas

  2. Pharma Algorithms Classification SAR ► Based on recursive partitioning Groups compounds into classes Aims at differentiating biol. mechanisms ► ►

  3. 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 ► ►

  4. 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

  5. Pharma Algorithms PhysChem Requirements for Non-substrates Negative charge Increases MV cut-off Decreases specificity Positive charge Decreases MV cut-off More data required

  6. 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

  7. 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

  8. Pharma Algorithms Examples of “Mechanistic Biophores” Similar skeletons were also identified for anthracyclines, talinolol, quinidine and etoposide groups.

  9. 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

  10. 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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