SIS i.s nii i i i t e r a c t i r~c tool for syiithcsis arid o p t i i i i c atioii of .scquciitial circiiits. (,'iiscii n sfntc t m i i s i t i o i i ta-1116 or a logic-lsuel drscriptiori of a scqurirtinl circuit, it produces (in optiini,-rd i i c t -l i s t i i i t h e target trchiiology roh ilr p rest ruing t h 6 .sf q iif 71 t i nl i rip ut -o ut y ut be li n ('io r. M a n y di,ffe re 71 t progrci iii .E n ii d nlgorith ins h a ut bet= ii i iitryrated into SIS, allouiiig t h e uscr to choost a i i i o i i y n unriety of trchiiiqncs (it each stage of t h c proctss. It is built 011 top of ~I I S I I [:?I a n d iiicliidt=s all ( c o i i i b i i i n - tioiial) optiiiiizatzon fechiriques t h e r e i n as w f l l as inaiiy eiihaiicemerits. SIS s e r i i m ( i s both a franrework ruithziiii~hich iurious algorithrirs c a n br trsttd arid compared. arid as a t o o l for autonicttic ,syiifhcsis a n d optinii-ntioir of seqiieiitinl carcu2t.s. This paper provides a n o i i c r i l i e~ of SIS: i n p u t specificntiori. STC; (sfate traiisztioii g r a p h ) i n n nip ul at 2 o n , a n d 11 t i~l logic opt ini c a t i o 71 n n d ut= rificat i o ii alg o rith rn s.

The advent of three-dimensional (3D) molecular database searching motivates this investigation of how best to formulate queries for compounds likely to bind to an enzyme or receptor. 3D queries in the literature generally refer to simple topological features (e.g., nitrogen or phenyl). To better capture the chemist's intent and to find functionally equivalent but structurally diverse compounds, generalized chemical function definitions are proposed for hydrogen bond acceptors/donors, charge centers, and hydrophobes. Use of these function definitions in 5-HT3 antagonist and ACE inhibition queries is shown to identify dramatically more hits capable of forming the hypothesized interactions. Furthermore, false positives that have features inaccessible to the receptor are eliminated. Next, the literahre on intermolecular interaction energy is reviewed to determine what geometric tolerances are chemically reasonable in queries. Finally, it is shown that the commonly used distance constraints poorly distinguish conformers that do and do not superimpose well with receptor features. An altemative, the location constraint, is proposed. Queries for angiotensin I1 antagonism and HLE inhibition are described and used to search 203 000 compounds.

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