Subject: solvent/binding/logP/R3N

From: [email-masked] (Jonathan Baell)
Date: Fri, 24 Nov 95 13:38

Dear All,

A few questions:
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A: Does anyone have a pointer to a good general discussion of approaches 
to incorporate environmental effects on molecular conformation such as 
might be experienced in a protein binding site and in an aqueous 
solution): e.g the pros and cons of simple distance-dependent dielectric 
methods (incorporating a constant of 1 or maybe 4?/using MNDO ESP 
charges?); more complex continuum methods; explicit solvent molecule 
calculations; treatment of highly basic amino groups in a protein binding 
site.

B: Related to A; Didesmethylchlorpromazine binds much more poorly to some 
sites than chlorpromazine.  Its terminal amine (RCH2NH2) has been shown 
to be significantly more basic than that in chlorpromazine (RCH2NMe2) 
[which was unexpected as far as I'm concerned], so desolvation problems 
may account for its weaker activity, or perhaps loss of favourable 
binding by the two methyl groups; but has there been discussion in the 
literature on the general principles of alkyl-NH2 versus alkyl-NMe2 
receptor-ligand effects, two groups which are highly prevalent in 
biologically active molecules?  

C: I have seen a number of studies where a linear relationship has been 
reported between nematocidal activity of C. elegans and affinity at 
binding sites in C. elegans, suggesting an absence of a lipophilic effect 
on transport, which is surprising for a whole organism assay if 
membrane-transport is required to reach the active site, and one would 
usually expect this to be the case.  The dataset in these cases has a 
reasonable spread of logP values.  The nature of these studies is such 
that the nematode is subjected continuously to toxin over a long time 
(16h), rather than as a bolus-type dose.  Can anyone point me to a good 
discussion of the relationship between time/dosage regimen and 
logP/activity, and why the nature of an assay such as the C. elegans one 
cited above might minimize lipophilicity as being an observable modulator 
of toxicity? 

D (and potentially paradoxical c.f. question C): For a certain group of 
compounds, we have the following QSAR for larvicidal activity for a 
particular species of parasitic nematode:

pLD50 = 2.11xpi - 0.782xpi^2 + 4.79

95%CI     0.72      0.21           0.49

T value   6.95      -8.92
n=10, s=0.205, Table T-test 2.37 (95%)
Y-mean=5.469, Y-variance = 0.833
Variance explained by regression=95%
F-ratio= 70.6, r=0.976, F(2,7,0.01)=9.55

What concerns me is the slope of 2.11.  What does this mean biologically? 
 I thought the slope in such equations was at most around unity for 
hydrophobically sensitive systems.  Could this value be explained by 
contributions of a substituent both to molecular lipophilicity (transport 
in vivo) and to binding to a localised hydrophobic pocket?

The assay involves continuous exposure to active constituent in an agar 
environment over several days.
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Any input would be greatly appreciated on any of these questions 
(including an internet address for a good QSAR discussion group, if there 
is one)

Jonathan Ball

email:    [email-masked] or [email-masked]