motecules ISSN 1420-3049 hp ve mdpi org, Lead Informatics, AstraZeneca RAD Molndal, $-43183 Mblndal, Sweden. Tel. +46 (0)31-776- "ax +46 (0)31-776-3792, e-mail: tudor oprea/@astrazeneca com, This article does not necessarily reflect the views of AstraZeneca. Received: 22 October 2001; in revised form 9 December 2001 / Accepted: 12 December 2001) Published: 31 January 2002 Abstract: Viral screening (VS) methods have emerged as an adaptive response to massive hroughput synthesis and screening technologies. Based on the structure-permeability paradigm, the Lipinski nile of five has become a standard property filtering protocol, for VS. Three possible VS soenarios with respect to optimising binding affinity and pharmacokinetic Properties are discussed. The parsimony principle for selecting candidate leads for further ‘optimisation is advocated eywords: ADME filter, combinatorial library design, drug discovery The Emergence of Virtual Sereeaing Massive throughput in synthesis and screening yields, on the average, hundreds of thousands of novel compounds that are synthesised, then screened for various properties, ranging from biological activity and solubility to metabolic stability and cytotoxicity. The economically-driven pressure to deliver the “frst-in-class” drug on the market has forced the pharmaceutical industry to embark in a costly, yot untested, drug discovery paradigm: Hunting forthe new gene, the new target, the new lead ‘compound, the new drug candidate, finally hunting for the new drug. Just as computational chemistry (Computer-aided drug design, molecular modelling, etc) was being hailed as the newest, safest and fastest method to put new chemical entities on the drug market in the late 1980s, so was combinatorial ‘chemistry (applied molecular evolution, multiple parallel synthesis, ete.), combined with high- ‘throughput screening (HTS), hailed as the newest, safest and fastest method in the mid-1990s. These2 Molecules 2002,7 technologies have partly delivered thir promise - but not in the manner intally described by SS cr failsafe sitco technology for drug discovery entopy and the diletric constant ae just two examples of subjects continously debated among experts, Beyond ligand-tecepttintarctions there's the complexity of multiple binding modes. accessible conformational states for_both ligand and -poepor, fini v8. selectvy, plasma protein binding, metabolic stability (ite ofrectvty and tun 9&0), absomption, dstnbution and excretion, as well as in vivo vs. in iro properties of model compounds. Such difculies are hardly sumountabc by any single computer-aided drug design software Even if sucessfil, such software could not provide generally applicable models due tothe inability of statistically trained models to provide trustworthy forecasts for unknown (previously n0t- seen-by-the-mode!) classes of compounds inthe combinatorial chemistry fel, differences inthe reactivity of similar, yet diverse reagents, dat often leas to impure, or nota all synthesized, compounds, as well asthe reality of inadequate, or missing, synthetic blocks (2), have resled in modertly succesful lead-finding. combinatorial libraries (3), focused more on forming carbon-eteroatom [4] bonds, and less on forming carbon- carbon [5] bonds. On the HTS side, took several years o realise that compound mixtures do ot yield ‘lable results, compared io one compound per well, and that screening potentially reactive species is too offen 2 cause of false hts (6), Furthermore, single dosesngle test procedures require repeat ‘expenments, in order to eliminate the false_positives and to confirm the structure and biological sxtivity ofthe HTS hits. The stability of the compounds in solid form, or in solution, coupled with the compounds’ availablity for future HTS, have added enough technical hurdles that might even slow down, not acelerat, the process of drug discovery. As increased awareness of these technological shortcor ;_permeates the computational, sombinatoral and medicinal chemistry communities, carefully planned strategies emerge. For example, the choice of reagents in synthesis planing is often performed via genet algoritns(7] or Statistical molecular design [8], whereby multifactorial response surfaces are optimised — all inthe context of tamget-related library design, whenever ‘three-dimensional target information is available. Permeability and solubility, key properties required for orally available compounds (9, are Increasingly being screened for with computational and experimental methods (10) prior te choosing >} Gandidate leads for further optimisation. Due to their impact on the successful progression of drug 500, CLOGP > 5, HDO > 5, and HAC > 10, may result in compounds with poor permeability | (exceptions are actively transported |-* compounds and peptides). The “rule of 5” (ROS) probability scheme hhad a major impact in the pharmaceutical industy, as most managers realised that duc tot simplicity, could be implemented carly on sn drug discovery, and potentially increase the chance of sucess in dg dasavery Pros asian anabfot Seti towed ‘comgvontswit piail BY We note here that, while very popular in recent literature (21-22), the polar moleculag of | suf. area (PSA is Siretly comelated with the sum of HDO.and HAC, ie. its a ROS-compaible descriptor. ser ception of CLOGP, all other ROS crits are ave since they can be secu cue for alas eating om the ects inter words ports cman “in which produets are generated in silico from alist of reagents (24) ~ provided that those moietics ‘s @ or lost during the “virtual reactions” are accounted for Rapid methods for estimating phobic library i