QSAR of Pgp efflux

1
QSAR of Pgp efflux

• John Dearden
• School of Pharmacy Chemistry
• Liverpool John Moores University
• Byrom Street, Liverpool L3 3AF, U.K.
• E-mail j.c.dearden_at_livjm.ac.uk

2
Anticipated Molecular Requirements

• No specific sub-structures needed
• No specific molecular shape(s)
• General molecular interactions likely to be
  involved (H-bonding, polarity, van der Waals
  forces, etc.)

3
Österberg Norinder, Eur. J. Pharm. Sci. 10
(2000) 295

• PLS analysis of 22 diverse drugs with
  P-glycoprotein-associated ATPase activity
• Found molecular surface area, hydrogen bonding
  and polarisability to be important.
• r2 0.776 Q2 0.742 s 0.422 F 41.5
• (one outlier omitted from correlation)

4
Dearden et alProc. Brit. Pharm. Conf. (2001) 219

• QSAR analysis of 22 diverse drugs with
  P-glycoprotein-associated ATPase activity
• log 1/Km 0.160 1c 0.170 Dx - 0.160 Dz 2.87
• r2 0.827 Q2 0.701 s 0.414 F 28.6
• (no outliers)

5
Dearden and ScottProc. Brit. Pharm. Conf. (2002)

• QSAR analysis of P-glycoprotein-regulated brain
  penetration of 22 diverse drugs. (Data from
  Ayrton Morgan, Xenobiotica 31 (2001) 469,
  involving the use of the Pgp-knockout mouse).
  Molecular weights range from 285 (morphine) to
  1202 (cyclosporin).

6
Dearden and ScottProc. Brit. Pharm. Conf. (2002)

• log R(-/) 0.113 3cvp 22.6 a/V - 0.104
  CtSdssC
• - 0.0435 Ncirc -
  0.317
• n 22 r2 0.854 Q2 0.788 s 0.182 F
  24.9
• External validation by leaving 5 out (4 times),
• s 0.181, 0.167, 0.208, 0.190.
• Also 100 randomisations carried out, max r2
  0.520, mean r2 0.186.

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Meaning of descriptors

• 3cvp size/branching
• a/V polarisability
• CtSdssC polarisability (?)
• Ncirc size (flat hydrophobic area?)

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Conclusions

• Descriptors are non-specific
• Size important
• Polarisability important (linked to size?)
• Polarity important
• No evidence of H-bonding found by us
  (contrast Österberg Norinder)