31-1
\.ill. I;'
An Analysis of Biological Linear Free-Energy Relationships
111: ~ i iearlier ieport' ail iiiitial attempt \va- imide ti) place niniiy of the current physicochemical upproache. t o the itudy of drug actioii into a. genernl frame of reference. The approach talieii IT ~ i -restricted t o :I con-ideration of drug-receptor interaction*, :i- i* the preient one, ;tnd drug reipoti-e hcing directly related to the free energy for the formation of a pharmacologically iinport tint drug-receptor c o n i j ~ l c ~ I:ollowing . n procedure outiined by T,efflcl* atid Gr~tn\vitld,~ the e-mitial free-etiergy ch:rnge TV:I*~ i n first a~~proxim:itiori, -eparated into iiidrperideiit electronic AGe, desolvatioii XP, and *teric AGs component-.
>I,{ = A(le
+ A(rCl + A(,- +
/\
(1)
111 t hi5 exprezsioii. t h e free-energy coiiiponciit due t I J po,zible coiifomni:ttioi~:tl change- of ;I given receptor hub-timce is included in the coriytaiit Ii along with :ill interaction trrmi. The iub*cript t2 tle-igri:itc- that for a seriei of AT conij)ouiid* t h e i ~will ~ h r :L wt of I I equaI/ tioris, z.e., S = I , 2 , Bused on rrcc3t orie- of c1ieniic:il re:icttvity' :\rid de~olvatiori,ieach inteructinp pair of atom ociated with drug : i d receptor, i e-pectively, could i;~idt o contribute independently to the electronic and deiolvation free-energy eomporic~nt-. By :\nalogy with the lladelung c -taut u-ccI i n cry~tnllography." :ind t)ecausc of the coiiformutioii, c.nch at of h i r i g aciigiied :I coii-t:Iiit chaixcteri+tic of i t 1oc;ttion in thc c--eiiti:d til ug 1 w q ) t o t . comple\. Thu-, I he ie*~icctiv(~ tcriiis 111 ecl 1 l ) c ~ 3 0 1 i r c ~
.I,
=
XE(Lr.+ I,, + I
$
I ,
)
+ /
