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Make Way for Virtual Screening Drug Discovery Make Way for Virtual Screening By Tim Cheeseright Virtual screening is being hailed by some as a superior method of and Robert Scoffin at evaluating compounds compared to high throughput screening. However, Cresset BioMolecular Discovery Ltd it’s still important to choose wisely between a ligand- or protein-based model template, as both can be prone to mishandling Over the last 20 years, high throughput screening selection of compounds to synthesise. Whatever the (HTS) has been the standard method of discovering database that is screened, virtual screening results in new active chemical matter. However, conducting a focused set of compounds for wet screening in high a high throughput screen of a large compound information content assays. collection against a given drug target is a complex, time-consuming and expensive process with no Quality for Less guarantee of success. By contrast, virtual screening is an effective and cheaper method of narrowing down One of the key drivers towards the adoption of a large compound collection to a smaller focused set, virtual screening as the method of choice for with a higher chance of hitting the target. starting discovery projects is the desire for high- quality biological data on all hit molecules at a Virtual screening is a computational method for fraction of the cost of HTS. Virtual screening provides evaluating a large number of compounds in order a fast, effective and inexpensive way of triaging to assess whether they are likely to be active at a large databases of compounds to get a small biological target of interest. It is also an effective number that can be assayed intensively, giving technique for discovering new hits, or for identifying high-quality data. a back-up series for a discovery project. Unlike an HTS campaign, a virtual screen requires some Outsourcing a virtual screening project to a specialist starting information before it can begin; this has company will typically cost £10,000-20,000. Compared slowed its uptake as the default method for starting to the cost of a high throughput screen, which could discovery projects. But recent advances in protein cost in the region of £2 million, this is remarkably crystallography have narrowed the gap, thus enabling cost-effective. virtual screening to take its place as a full replacement for HTS. Choosing the Right Screening Method Traditionally, virtual screening would search a There are two main approaches to virtual screening: database of molecules comprising the structures ligand-based virtual screening and protein structure- of the millions of real compounds based virtual screening. The key difference between Keywords from a corporate collection, or from the two methods is whether the protein or the ligand vendors. As virtual screening methods is used as a model template against which potential High throughput screening and throughput have improved, so screening compounds can be virtually tested. If the (HTS) the size of the database that can interaction of a ligand with a protein is thought of as Virtual screening be screened has increased. Virtual a lock and key mechanism, then protein-based virtual Ligand-based screening is now being used to screen screening is the equivalent of taking the lock as the tens or hundreds of millions of virtual template, rather than the key. Protein structure-based compounds, created by enumerating a Field points combinatorial library or by decorating There are many pros and cons to ligand- and protein- Graphical processing units known scaffolds with novel side- based virtual screening, and both can be prone (GPUs) chains, resulting in a knowledge-based to mishandling. Each approach has its strengths, 16 Innovations in Pharmaceutical Technology Issue 45 IPT 45 2013.indd 16 30/05/2013 08:33 iptonline.com and the results obtained from either method Methods are usually based either on the finding of can be comparable and, in many cases, highly compounds in the database with a similar atomic complementary. structure to known actives, or upon discovering compounds that can make similar interactions with Protein Structure-Based Screening the protein as the known actives. In either case, the drug targets do not need to have an elucidated Protein structure-based screening, often referred to structure. This makes ligand-based virtual screening as ‘docking’, involves taking the structure of the target ideal for ion channels and G protein-coupled protein and calculating the binding energy for a series receptors, which represent the majority of of ligand structures in one or more poses. A pose is a drug targets. given conformation of the ligand in a docked position within the protein’s active site. Using atomistic methods for ligand-based virtual screening, such as ‘2D similarity’ or ‘substructure’ Theoretically, docking should be the method of searching, has long been used in conjunction with choice for all virtual screens. Docking can perform HTS to flesh out any new active molecule with very well if conducted by an expert on an amenable structure-activity relationship information. The protein target, but there are many situations where great advantage of these methods is the speed at it is not as effective as might be desired. A number which they can return compounds that have a high of challenges presented by this approach reduce its probability of being active. Unfortunately, the very effectiveness, and can lead to the use of ligand-based nature of these methods means that it is difficult methods in preference. to find actives that are truly novel. By definition, any compounds found are structurally similar to Firstly, it is most useful to consider the protein the query molecule, and hence are likely to share structure in a relevant activated state, but this is not any absorption, distribution, metabolism, excretion, always possible and where it could become a viable toxicity (ADMET) or intellectual property issues it option, the protein may contain flexible loops that may have. significantly alter the shape of the active site. In contrast to atomistic methods, ligand-based virtual Secondly, there are number of different approaches to screening approaches that mimic the interactions the computationally intensive process of determining of known actives with the protein in 3D, excel the poses to be scored. Each approach has certain at generating novel actives with the freedom to benefits in some circumstances, but knowing which is operate. However, using a 3D-based method does best for the current target is difficult to determine. slow down the rate at which compounds can be virtually screened. It also incurs an overhead in the Finally, there are a number of methods used to generation of the database in a 3D format through calculate a score for the generated poses. This is conformation exploration. Nonetheless, these usually a pseudo-binding energy score, and relies methods are quite capable of screening tens of heavily on the method that was used to parameterise millions of compounds in a short timeframe of the scoring function. No single scoring function 24 to 48 hours by deploying calculations to a performs well in all circumstances. Linux cluster. There are, therefore, many different docking methods; Historically, using a 3D ligand-based screening that is, combinations of pose generation and pose method meant using pharmacophores that were scoring. Each has its own strengths and weaknesses, defined as feature-based labels of the interactions and there is no clear ‘best’ docking method. This can of ligand and protein, to search for novel actives. leave the virtual screening practitioner in a quandary However, a desire for more physical-based methods over which method to choose. led to the use of the shape of the known active when bound to the protein, and a renaissance Ligand-Based Screening in 3D ligand-based screening. These simplistic physical models are now being superseded by Ligand-based virtual screening does not rely on the more detailed models that combine the shape of use of a protein structure to guide the process. The actives with physically derived features, such as the method depends on the assumption that an active electrostatic environment surrounding the active ligand or ligands will define the required features for molecule, to give new, high information content activity in general against the given target. pharmacophores. Innovations in Pharmaceutical Technology Issue 45 17 IPT 45 2013.indd 17 30/05/2013 08:33 iptonline.com Figure 1: Electrostatics Mean Realistic Pharmacophores Additionally, compounds with very similar shapes can 2D structures of show radically different biological properties, driven structurally diverse Developing a more realistic and descriptive by differing electrostatic or hydrophobic properties. bioisosteres both active at PDE3, pharmacophore requires using the electrostatic, A demonstration of this can be seen with a simple cAMP (the natural shape and hydrophobic properties of a molecule in series of substituted benzenes (see Figure 2). substrate) and combination in order to build up a detailed ‘protein’s- SKF93741, a PDE3 inhibitor. eye view’ of the molecule. These molecular fields Increasing Speed and Expanding Scope The field patterns yield an immense amount of information about the of the compounds reveal that they are properties of a ligand and the likely interactions Even with the use of field points, the computational biologically similar it will make with a protein. cost of calculating 3D molecular similarities means Source:
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