How Large Does a Compound Screening Collection Need To Be?

Abstract

Increasingly, chemical libraries are being produced which are focused on a biological target or group of related targets, rather than simply being constructed in a combinatorial fashion. A screening collection compiled from such libraries will contain multiple analogues of a number of discrete series of compounds. The question arises as to how many analogues are necessary to represent each series in order to ensure that an active series will be identified. Based on a simple probabilistic argument and supported by in-house screening data, guidelines are given for the number of compounds necessary to achieve a "hit", or series of hits, at various levels of certainty. Obtaining more than one hit from the same series is useful since this gives early acquisition of SAR (structure-activity relationship) and confirms a hit is not a singleton. We show that screening collections composed of only small numbers of analogues of each series are sub-optimal for SAR acquisition. Based on these studies, we recommend a minimum series size of about 200 compounds. This gives a high probability of confirmatory SAR (i.e. at least two hits from the same series). More substantial early SAR (at least 5 hits from the same series) can be gained by using series of about 650 compounds each. With this level of information being generated, more accurate assessment of the likely success of the series in hit-to-lead and later stage development becomes possible.

Les chimiothèques ciblant les interactions protéine-protéine

“…Par ailleurs, les taux de succès de cette approche globale sont plus faibles que prévus, surtout pour les cibles non traditionnelles [9]. Une alternative de plus en plus acceptée consiste à concevoir des chimiothèques focalisées [10,11]. Une chimiothèque focalisée est une collection de molécules chimiques dédiées à une cible ou un ensemble de cibles (généralement protéiques) appartenant au même espace chimique ou biologique [44,45].…”

Shaping a Screening File for Maximal Lead Discovery Efficiency and Effectiveness: Elimination of Molecular Redundancy

“…A cluster of X compounds isolated in chemical space within a certain similarity, represents, in the context of this work, X neighborhoods, where each of the X compounds has X-1 nearest neighbors. This is an important concept and distinction to make, as if clusters are treated as isolated objects, and no consideration given to their overlapping in chemical space, the results may be quite different 37 .Note that in contrast to others 37 we deliberately chose not to make the neighborhood size big enough to generate SAR directly from the HTS, as we felt that this was not the most efficient way to operate. We also note that our selection of an equal number of molecules in each neighborhood is consistent with the conclusions of Harper et al 36 So, Redundancy as we defined above is a compound specific property.…”

“…Thus, fourthly and finally, we introduce here for the first time the concept of molecular redundancy in order to answer this question. Our work builds on activity probability methodology introduced by Nilakantan et al, 35 which was further developed by Harper et al 36 and Lipkin et al 37 as well as work relating chemical similarity to biological activity by Hajduk and Martin 38 Our computational method enables us firstly to determine how many compounds in a given area of chemical space will be needed in order to generate at least one hit in HTS (see below) and secondly to select redundant compounds that are not required.…”

High Throughput Screening Approach to Lead Discovery

“…A recently reported probability analysis of historical data derived from screening focused libraries recommended a library size ranging from 200 to 650 compounds. Libraries of this size should be sufficient to provide minimum confirmatory SAR information (2-5 hits from the same chemical series) [98].…”