ReviewLead discovery using molecular docking
Introduction
Given the atomic resolution structure of a macromolecule, such as an enzyme, it should be possible to find novel molecules that bind to it, modulating its activity. This is the premise behind all structure-based ligand design and discovery efforts. Here we consider one aspect of this field: structure-based ligand discovery, emphasizing the screening of compound libraries using molecular docking.
The promise of docking is that the structure of the target will provide a template for the discovery of novel ligands, dissimilar to those previously known. One begins with a database of compounds and the structure of a receptor of interest and asks, ‘Of the compounds in the database, which is most likely to bind to the receptor?’ (Fig. 1). This apparently simple question disguises an enormous problem and a clever, if sometimes unsuccessful, strategy. The problem is that of predicting absolute binding affinities of many disparate molecules. Whereas predicting relative binding affinities for related molecules is possible, although time consuming, we have no reason to expect that we can predict absolute binding affinities for so many unrelated compounds. If docking has had an impact, it is because of its strategy of using databases of available compounds. This makes failure cheap; one simply goes to the next compound in a hit list. Docking for discovery is a screening technique: both false positives and false negatives are tolerated as long as true positives are found at a sufficiently high rate to justify the effort. How high should this hit rate be?
Section snippets
Comparing docking and high-throughput screening
Because high-throughput screening (HTS) is the dominant technique for pharmaceutical lead discovery, what level of hit-rate enhancement would be sufficient to justify pursuing structure-based docking? Indeed, if HTS is available, why do docking at all (Fig. 1)? Two recent studies begin to consider this question.
Using both HTS and virtual screening, inhibitors were sought for the type 2 diabetes target protein tyrosine phosphatase 1B (PTP1B) [1]. In the HTS experiments, a 400 000 compound
Recent applications of docking
Docking has been used to discover novel ligands for well over 30 targets. Work in the past year has continued to focus on enzymes (Table 1). The inhibitors discovered were novel, having little similarity to the known ligands. Most initial leads had affinities in the low-micromolar range. The new sulfonamide inhibitors of carbonic anhydrase II [3] are the exception—they are much more potent, but not completely novel. There has been an efflorescence of new docking methods in the past several
Integration of docking with design and virtual libraries
Can docking hits be turned into leads through synthetic elaboration? In several studies 5•., 10., the affinity of hits was improved by 10- to 1000-fold (Table 1), often through ‘classical’ structure-based techniques (i.e. beginning with a lead and using the complexed structure and chemical intuition to improve it). More sophisticated efforts have tried to include synthetic accessibility in the virtual screening from the beginning. In an effort to design novel CDK4 inhibitors, the de novo design
Technical advances in docking algorithms
Molecular docking continues to witness the introduction of new algorithms and programs—these are much needed given the weaknesses in conformational sampling and scoring. Along with efforts to improve established docking programs, such as autodock, dock, ecepp/prodock, flexx, flog, gold, green, icm, ludi, pro_leads, qxp and slide (reviewed in [21] and [22]), new docking programs have been published in the past year, including the eudoc algorithm [23], seed [24•], seeds [4•] and mm [25].
Two
The use of homology models in docking
For many interesting targets, an experimental structure is unavailable. In principle, homology modeling can calculate a structure for use in drug discovery [42], thereby dramatically increasing the number of targets to which docking might be applied. How reliable are these models for docking? This question cannot be answered definitively, but some tentative points may be made.
Several groups have used homology models to design or discover ligands for target proteins. Indeed, of the 12 docking
Hit conformation and promiscuous inhibitors
As is well known to screeners and medicinal chemists, many HTS hits are promiscuous and non-‘drug-like’. This can also be true of docking hits. Whereas detailed testing to confirm a hit routinely occurs in HTS projects, docking hits are not always confirmed as carefully. In our own painful experience, this can lead to artifacts that are confusing and time consuming. Every effort should be made to remove what we have come to call ‘pathological’ inhibitors from docking hit lists.
We can consider
Conclusions
The recent explosion of protein structures, and the advent of the genome projects, has renewed interest in using structure-based docking for early-phase lead discovery. Database docking has made considerable progress in the past decade, but it remains a screening technique. As such, current docking programs will dissatisfy investigators interested in definitive predictions of new inhibitors, and predictions of geometries can still go wildly wrong. In favorable circumstances, docking screens can
Acknowledgements
Supported by GM59957 (to BKS). SLM is a Northwestern University Presidential Scholar, and is partly supported by T32-GM08152 (K Mayo, PI) and a PhRMA Foundation Medical Student Fellowship. We are grateful to David Lorber for many discussions.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Now in press
The work referred to in the text as (R Powers, BK Shoichet, unpublished data) is now published. The work referred to in the text as (BW & BKS, unpublished data) is now in press
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