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Docking and scoring in virtual screening for drug discovery: methods and applications

Key Points

  • Computational methodologies have become a crucial component of many drug discovery programmes, from hit identification to lead optimization and beyond.

  • One key such methodology — docking of small molecules to protein binding sites — was pioneered during the early 1980s, and remains a highly active area of research.

  • The docking process involves the prediction of ligand conformation and orientation (or posing) within a targeted binding site. In general, there are two aims of docking studies: accurate structural modelling and correct prediction of activity.

  • Docking is generally devised as a multi-step process in which each step introduces one or more additional degrees of complexity. The process begins with the application of docking algorithms that pose small molecules in the active site. These algorithms are complemented by scoring functions that are designed to predict the biological activity through the evaluation of interactions between compounds and potential targets.

  • This article reviews basic concepts and specific features of small-molecule–protein docking methods and several selected applications, with particular emphasis on hit identification and lead optimization.

  • We attempt to distinguish between the problems of docking compounds into target sites and of scoring docked conformations, because the available data indicate that numerous robust and accurate docking algorithms are available, whereas imperfections of scoring functions continue to be a major limiting factor.


Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization. Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors. Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes. Here, we review key concepts and specific features of small-molecule–protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches.

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Figure 1: Grid representations.
Figure 2: Electrostatic potential of a bound inhibitor.
Figure 3: Modelling molecular recognition.
Figure 4: Complexity of protein–ligand interactions.
Figure 5: Design of specific inhibitors.

Accession codes


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H.D. and J.R.F. contributed equally to this paper. This manuscript is dedicated to Wolfram Saenger, Free University Berlin, on the occasion of his sixty-fifth birthday.

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Correspondence to Jürgen Bajorath.

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The process of determining whether a given conformation and orientation of a ligand fits the active site. This is usually a fuzzy procedure that returns many alternative results.


Both posing and ranking involve scoring. The pose score is often a rough measure of the fit of a ligand into the active site. The rank score is generally more complex and might attempt to estimate binding energies.


A more advanced process than pose scoring that typically takes several results from an initial scoring phase and re-evaluates them. This process usually attempts to estimate the free energy of binding as accurately as possible. Although the posing phase might use simple energy calculations (electrostatic and van der Waals), ranking procedures typically involve more elaborate calculations (perhaps including properties such as entropy or explicit solvation).


All degrees of freedom involved in the process of placing one molecule relative to another. For example, for two rigid molecules the pose space simply consists of relative orientations. When one of the molecules, the ligand, is allowed to be flexible, the pose space comprises both the conformational space of the ligand and orientational space of ligand and receptor.


A function expressing the energy of a system as a sum of diverse molecular mechanics (or other) terms.


Entropy associated with a rotatable bond in a molecule. Immobilization of a rotatable bond on binding leads to loss of its torsional (or rotational) entropy.


Determination of parameter values for a chosen (linear or nonlinear) function to best fit a set of observations.


(PMF). In the context of docking and scoring, PMFs are derived from statistical analysis of experimentally observed distributions and frequencies of specific atom-pair interactions in a large collection of protein–ligand structures. Interaction potentials between each atom pair in two molecules (for example, ligand and protein) approximate the free energy of each pair-wise interaction as a function of inter-atomic distance.


Mathematical analysis based on two classes of data and two independent variables (a, b) that attempts to find a line that best separates the data. This line is orthogonal to the discriminant function that is a linear combination of the original variables, in this case: F = caa + cbb (ca, cb; coefficients).


The spatial arrangement of atoms or groups in a molecule known or predicted to be responsible for specific biological activity.


Holo-: ligand-bound form of an enzyme; apo-: uncomplexed form. The original definitions referred to enzymes and cofactors, rather than ligands, but ligands and cofactors are often synonymously used.


An oscillation in which all particles of a system move with the same frequency and phase.

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Kitchen, D., Decornez, H., Furr, J. et al. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3, 935–949 (2004).

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