Bibliography of computer-aided Drug Design

Updated on 7/18/2014. Currently 2130 references

Docking / Reviews

2013 / 2012 / 2011 / 2010 / 2009 / 2008 / 2007 / 2006 / 2004 / 2003 / 2002 /


2013

  • Latest developments in molecular docking: 2010-2011 in review.
    Yuriev, Elizabeth and Ramsland, Paul A
    Journal of molecular recognition : JMR, 2013, 26(5), 215-239
    PMID: 23526775     doi: 10.1002/jmr.2266
     
    The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. The main developments in docking in this period, covered in this review, are receptor flexibility, solvation, fragment docking, postprocessing, docking into homology models, and docking comparisons. Several new, or at least newly invigorated, advances occurred in areas such as nonlinear scoring functions, using machine-learning approaches. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design. Where appropriate, we refer readers to exemplar case studies. Copyright

2012

  • Accessible high-throughput virtual screening molecular docking software for students and educators.
    Jacob, Reed B. and Andersen, Tim and McDougal, Owen M.
    PLoS computational biology, 2012, 8(5), e1002499
    PMID: 22693435     doi: 10.1371/journal.pcbi.1002499
     
    We survey low cost high- throughput virtual screening (HTVS) computer programs for instructors who wish to demonstrate molecular docking in their courses. Since HTVS programs are a useful adjunct to the time consuming and expensive wet bench experiments necessary to discover new drug therapies, the topic of molecular docking is core to the instruction of biochemistry and molecular biology. The availability of HTVS programs coupled with decreasing costs and advances in computer hardware have made computational approaches to drug discovery possible at institutional and non-profit budgets. This paper focuses on HTVS programs with graphical user interfaces (GUIs) that use either DOCK or AutoDock for the prediction of DockoMatic, PyRx, DockingServer, and MOLA since their utility has been proven by the research community, they are free or affordable, and the programs operate on a range of computer platforms.

  • Modeling peptide-protein interactions.
    London, Nir and Raveh, Barak and Schueler-Furman, Ora
    Methods in molecular biology (Clifton, N.J.), 2012, 857, 375-398
    PMID: 22323231     doi: 10.1007/978-1-61779-588-6_17
     
    Peptide-protein interactions are prevalent in the living cell and form a key component of the overall protein-protein interaction network. These interactions are drawing increasing interest due to their part in signaling and regulation, and are thus attractive targets for computational structural modeling. Here we report an overview of current techniques for the high resolution modeling of peptide-protein complexes. We dissect this complicated challenge into several smaller subproblems, namely: modeling the receptor protein, predicting the peptide binding site, sampling an initial peptide backbone conformation and the final refinement of the peptide within the receptor binding site. For each of these conceptual stages, we present available tools, approaches, and their reported performance. We summarize with an illustrative example of this process, highlighting the success and current challenges still facing the automated blind modeling of peptide-protein interactions. We believe that the upcoming years will see considerable progress in our ability to create accurate models of peptide-protein interactions, with applications in binding-specificity prediction, rational design of peptide-mediated interactions and the usage of peptides as therapeutic agents.

  • Flexibility and binding affinity in protein-ligand, protein-protein and multi-component protein interactions: limitations of current computational approaches.
    Tuffery, Pierre and Derreumaux, Philippe
    Journal of the Royal Society, Interface / the Royal Society, 2012, 9(66), 20-33
    PMID: 21993006     doi: 10.1098/rsif.2011.0584
     
    The recognition process between a protein and a partner represents a significant theoretical challenge. In silico structure-based drug design carried out with nothing more than the three-dimensional structure of the protein has led to the introduction of many compounds into clinical trials and numerous drug approvals. Central to guiding the discovery process is to recognize active among non-active compounds. While large-scale computer simulations of compounds taken from a library (virtual screening) or designed de novo are highly desirable in the post-genomic area, many technical problems remain to be adequately addressed. This article presents an overview and discusses the limits of current computational methods for predicting the correct binding pose and accurate binding affinity. It also presents the performances of the most popular algorithms for exploring binary and multi-body protein interactions.

2011

  • Darwinian Docking.
    Kuntz, Irwin D
    Journal of computer-aided molecular design, 2011, 26(1), 73-75
    PMID: 22143893     doi: 10.1007/s10822-011-9503-4
     
    The Darwinian model of evolution is an optimization strategy that can be adapted to docking. It differs from the common use of genetic algorithms, primarily in its acceptance of diverse solutions over finding "global" optima. A related problem is selecting compounds using multiple criteria. I discuss these ideas and present the outlines of a protocol for selecting "hits" and "leads" in drug discovery.

  • Accounting for induced-fit effects in docking: what is possible and what is not?
    Sotriffer, Christoph A.
    Current topics in medicinal chemistry, 2011, 11(2), 179-191
    PMID: 20939789    
     
    Proteins can undergo a variety of conformational changes upon ligand binding. Although different mechanisms may play a role, the phenomenon is commonly referred to as induced fit to indicate that the tight structural complementarity of the interaction partners is a consequence of the binding event. Docking methods need to take into account this ability of the ligand and the protein to mutually adapt to each other when forming a complex. Handling the ligand as flexible is already common practice in docking applications. This is not yet the case for the protein. In fact, the accurate prediction of protein conformational changes upon ligand binding is still a major challenge, even more if computational speed is an issue, as for example in virtual screening applications. However, significant progress has been made over the past years and many valuable approaches have become available to address the protein flexibility problem and to provide more reliable docking predictions for complexes governed by significant induced-fit effects. This review provides a brief overview of the current situation, the most recent advances, and the remaining limitations of flexible protein docking, with particular focus on approaches handling protein flexibility simultaneously with ligand placement in the docking process.

  • Challenges and advances in computational docking: 2009 in review.
    Yuriev, Elizabeth and Agostino, Mark and Ramsland, Paul A
    Journal of molecular recognition : JMR, 2011, 24(2), 149-164
    PMID: 21360606     doi: 10.1002/jmr.1077
     
    Docking is a computational technique that places a small molecule (ligand) in the binding site of its macromolecular target (receptor) and estimates its binding affinity. This review addresses methodological developments that have occurred in the docking field in 2009, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. These developments aim to address the main challenges of docking: receptor representation (such aspects as structural waters, side chain protonation, and, most of all, flexibility (from side chain rotation to domain movement)), ligand representation (protonation, tautomerism and stereoisomerism, and the effect of input conformation), as well as accounting for solvation and entropy of binding. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design.

2010

  • Structural ensemble in computational drug screening.
    Fukunishi, Yoshifumi
    Expert opinion on drug metabolism & toxicology, 2010, 6(7), 835-849
    PMID: 20465522     doi: 10.1517/17425255.2010.486399
     
    Importance of the field: Structure-based in silico drug screening is now widely used in drug development projects. Structure-based in silico drug screening is generally performed using a protein-compound docking program and docking scoring function. Many docking programs have been developed over the last 2 decades, but their prediction accuracy remains insufficient. Areas covered in this review: This review highlights the recent progress of the post-processing of protein-compound complexes after docking. What the reader will gain: These methods utilize ensembles of docking poses of compounds to improve the prediction accuracy for the ligand-docking pose and screening results. While the individual docking poses are not reliable, the free energy surface or the most probable docking pose can be estimated from the ensemble of docking poses. Take home message: The protein-compound docking program provides an arbitral rather than a canonical ensemble of docking poses. When the ensemble of docking poses satisfies the canonical ensemble, we can discuss how these post-docking analysis methods work and fail. Thus, improvements to the docking software will be needed in order to generate well-defined ensembles of docking poses.

  • Advances and challenges in protein-ligand docking.
    Huang, Sheng-You and Zou, Xiaoqin
    International journal of molecular sciences, 2010, 11(8), 3016-3034
    PMID: 21152288     doi: 10.3390/ijms11083016
     
    Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions-the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion.

  • Virtual screening: an endless staircase?
    Schneider, Gisbert
    Nature reviews. Drug discovery, 2010, 9(4), 273-276
    PMID: 20357802     doi: 10.1038/nrd3139
     
    Computational chemistry - in particular, virtual screening - can provide valuable contributions in hit- and lead-compound discovery. Numerous software tools have been developed for this purpose. However, despite the applicability of virtual screening technology being well established, it seems that there are relatively few examples of drug discovery projects in which virtual screening has been the key contributor. Has virtual screening reached its peak? If not, what aspects are limiting its potential at present, and how can significant progress be made in the future?

2009

  • Docking Screens: Right for the Right Reasons?
    Kolb, Peter and Irwin, John J
    Current topics in medicinal chemistry, 2009, 9(9), 755-770
     
    Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.

  • Docking and chemoinformatic screens for new ligands and targets
    Kolb, Peter and Ferreira, Rafaela S and Irwin, John J and Shoichet, Brian K
    Current Opinion in Biotechnology, 2009, 20(4), 429-436
    doi: 10.1016/j.copbio.2009.08.003
     
    ... rate of 24% [19 * ] (Figure 3). Intriguingly, five of these were inverse agonists, as was the ligand bound in the X-ray structure, carazolol, against which the screen occurred. ... This is borne out in a community-wide, blind assessment (GPCR Dock 2008 [41]) of the prediction of the ...

  • Docking and chemoinformatic screens for new ligands and targets
    Kolb, Peter and Ferreira, Rafaela S and Irwin, John J and Shoichet, Brian K
    Current Opinion in Biotechnology, 2009, 20(4), 429-436
    doi: 10.1016/j.copbio.2009.08.003
     
    ... rate of 24% [19 * ] (Figure 3). Intriguingly, five of these were inverse agonists, as was the ligand bound in the X-ray structure, carazolol, against which the screen occurred. ... This is borne out in a community-wide, blind assessment (GPCR Dock 2008 [41]) of the prediction of the ...

  • Managing protein flexibility in docking and its applications.
    B-Rao, Chandrika and Subramanian, Jyothi and Sharma, Somesh D
    Drug discovery today, 2009, 14(7-8), 394-400
    PMID: 19185058     doi: 10.1016/j.drudis.2009.01.003
     
    Docking, virtual screening and structure-based drug design are routinely used in modern drug discovery programs. Although current docking methods deal with flexible ligands, managing receptor flexibility has proved to be challenging. In this brief review, we present the current state-of-the-art for computationally handling receptor flexibility, including a novel statistical computational approach published recently. We conclude, from a comparison of the different approaches, that a combination of methods is likely to provide the most reliable solution to the problem of finding the right protein conformation for a given ligand.

  • Docking, virtual high throughput screening and in silico fragment-based drug design.
    Zoete, Vincent and Grosdidier, Aurélien and Michielin, Olivier
    Journal of cellular and molecular medicine, 2009, 13(2), 238-248
    PMID: 19183238     doi: 10.1111/j.1582-4934.2008.00665.x
     
    The drug discovery process has been profoundly changed recently by the adoption of computational methods helping the design of new drug candidates more rapidly and at lower costs. In silico drug design consists of a collection of tools helping to make rational decisions at the different steps of the drug discovery process, such as the identification of a biomolecular target of therapeutical interest, the selection or the design of new lead compounds and their modification to obtain better affinities, as well as pharmacokinetic and pharmacodynamic properties. Among the different tools available, a particular emphasis is placed in this review on molecular docking, virtual high-throughput screening and fragment-based ligand design.

2008

  • Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection-what can we learn from earlier mistakes?
    Kirchmair, Johannes and Markt, Patrick and Distinto, Simona and Wolber, Gerhard and Langer, Thierry
    Journal of computer-aided molecular design, 2008, 22(3-4), 213-228
    PMID: 18196462     doi: 10.1007/s10822-007-9163-6
     
    Within the last few years a considerable amount of evaluative studies has been published that investigate the performance of 3D virtual screening approaches. Thereby, in particular assessments of protein-ligand docking are facing remarkable interest in the scientific community. However, comparing virtual screening approaches is a non-trivial task. Several publications, especially in the field of molecular docking, suffer from shortcomings that are likely to affect the significance of the results considerably. These quality issues often arise from poor study design, biasing, by using improper or inexpressive enrichment descriptors, and from errors in interpretation of the data output. In this review we analyze recent literature evaluating 3D virtual screening methods, with focus on molecular docking. We highlight problematic issues and provide guidelines on how to improve the quality of computational studies. Since 3D virtual screening protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of test sets on the outcome of evaluations. Moreover, we investigate the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D virtual screening methods. Furthermore, we review the significance and suitability of RMSD as a measure for the accuracy of protein-ligand docking algorithms and of conformational space sub sampling algorithms.

  • Protein-ligand Docking: A Review of Recent Advances and Future Perspectives
    Pujadas, Gerard and Vaque, Montserrat and Ardevol, Anna and Blade, Cinta and Salvado, M. J. and Blay, Mayte and Fernandez-Larrea, Juan and Arola, Lluis
    Current Pharmaceutical Analysis, 2008, 4(1), 1-19
    doi: 10.2174/157341208783497597
     
    Abstract: Understanding the interactions between proteins and ligands is crucial for the pharmaceutical and functional food industries. The experimental structures of these protein/ ligand complexes are usually obtained, under highly expert control, by time- ...

  • Protein-ligand Docking: A Review of Recent Advances and Future Perspectives
    Pujadas, Gerard and Vaque, Montserrat and Ardevol, Anna and Blade, Cinta and Salvado, M. J. and Blay, Mayte and Fernandez-Larrea, Juan and Arola, Lluis
    Current Pharmaceutical Analysis, 2008, 4(1), 1-19
    doi: 10.2174/157341208783497597
     
    Abstract: Understanding the interactions between proteins and ligands is crucial for the pharmaceutical and functional food industries. The experimental structures of these protein/ ligand complexes are usually obtained, under highly expert control, by time- ...

  • Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go.
    Moitessier, N and Englebienne, P and Lee, D and Lawandi, J and Corbeil, C R
    British journal of pharmacology, 2008, 153 Suppl 1, S7-26
    PMID: 18037925     doi: 10.1038/sj.bjp.0707515
     
    Accelerating the drug discovery process requires predictive computational protocols capable of reducing or simplifying the synthetic and/or combinatorial challenge. Docking-based virtual screening methods have been developed and successfully applied to a number of pharmaceutical targets. In this review, we first present the current status of docking and scoring methods, with exhaustive lists of these. We next discuss reported comparative studies, outlining criteria for their interpretation. In the final section, we describe some of the remaining developments that would potentially lead to a universally applicable docking/scoring method.

  • An improved relaxed complex scheme for receptor flexibility in computer-aided drug design.
    Amaro, Rommie E and Baron, Riccardo and McCammon, J Andrew
    Journal of computer-aided molecular design, 2008, 22(9), 693-705
    PMID: 18196463     doi: 10.1007/s10822-007-9159-2
     
    The interactions among associating (macro)molecules are dynamic, which adds to the complexity of molecular recognition. While ligand flexibility is well accounted for in computational drug design, the effective inclusion of receptor flexibility remains an important challenge. The relaxed complex scheme (RCS) is a promising computational methodology that combines the advantages of docking algorithms with dynamic structural information provided by molecular dynamics (MD) simulations, therefore explicitly accounting for the flexibility of both the receptor and the docked ligands. Here, we briefly review the RCS and discuss new extensions and improvements of this methodology in the context of ligand binding to two example targets: kinetoplastid RNA editing ligase 1 and the W191G cavity mutant of cytochrome c peroxidase. The RCS improvements include its extension to virtual screening, more rigorous characterization of local and global binding effects, and methods to improve its computational efficiency by reducing the receptor ensemble to a representative set of configurations. The choice of receptor ensemble, its influence on the predictive power of RCS, and the current limitations for an accurate treatment of the solvent contributions are also briefly discussed. Finally, we outline potential methodological improvements that we anticipate will assist future development.

2007

  • Ligand docking and structure-based virtual screening in drug discovery.
    Cavasotto, Claudio N and Orry, Andrew J W
    Current topics in medicinal chemistry, 2007, 7(10), 1006-1014
    PMID: 17508934    
     
    Ligand-docking-based methods are starting to play a critical role in lead discovery and optimization, thus resulting in new 'drug-candidates'. They offer the possibility to go beyond the pool of existing active compounds, and thus find novel chemotypes. A brief tutorial on ligand docking and structure-based virtual screening is presented highlighting current problems and limitations, together with the most recent methodological and algorithmic developments in the field. Recent successful applications of docking-based tools for hit discovery, lead optimization and target-biased library design are also presented. Special consideration is devoted to ongoing efforts to account for protein flexibility in structure-based virtual screening.

  • Lessons in molecular recognition. 2. Assessing and improving cross-docking accuracy.
    Sutherland, Jeffrey J and Nandigam, Ravi K and Erickson, Jon A and Vieth, Michal
    Journal of chemical information and modeling, 2007, 47(6), 2293-2302
    PMID: 17956084     doi: 10.1021/ci700253h
     
    Docking methods are used to predict the manner in which a ligand binds to a protein receptor. Many studies have assessed the success rate of programs in self-docking tests, whereby a ligand is docked into the protein structure from which it was extracted. Cross-docking, or using a protein structure from a complex containing a different ligand, provides a more realistic assessment of a docking program's ability to reproduce X-ray results. In this work, cross-docking was performed with CDocker, Fred, and Rocs using multiple X-ray structures for eight proteins (two kinases, one nuclear hormone receptor, one serine protease, two metalloproteases, and two phosphodiesterases). While average cross-docking accuracy is not encouraging, it is shown that using the protein structure from the complex that contains the bound ligand most similar to the docked ligand increases docking accuracy for all methods ("similarity selection"). Identifying the most successful protein conformer ("best selection") and similarity selection substantially reduce the difference between self-docking and average cross-docking accuracy. We identify universal predictors of docking accuracy (i.e., showing consistent behavior across most protein-method combinations), and show that models for predicting docking accuracy built using these parameters can be used to select the most appropriate docking method.

2006

  • Identification and Evaluation of Molecular Properties Related to Preclinical Optimization and Clinical Fate
    Wang, Zhanli and Huo, Jianxin and Sun, Lidan and Wang, Yongfu and Jin, Hongwei and Yu, Hui and Zhang, Liangren and Zhou, Lishe
    Current medicinal chemistry, 2006, 13(1), 214-227
    PMID: 21595631     doi: 10.2174/092986706775197999
     
    ... Page 3. Privileged Structures as leads in Medicinal Chemistry ... 2), Ki

  • Identification and Evaluation of Molecular Properties Related to Preclinical Optimization and Clinical Fate
    Wang, Zhanli and Huo, Jianxin and Sun, Lidan and Wang, Yongfu and Jin, Hongwei and Yu, Hui and Zhang, Liangren and Zhou, Lishe
    Current medicinal chemistry, 2006, 13(1), 214-227
    PMID: 21595631     doi: 10.2174/092986706775197999
     
    ... Page 3. Privileged Structures as leads in Medicinal Chemistry ... 2), Ki

  • Scoring functions for protein-ligand docking.
    Jain, Ajay N
    Current Protein & Peptide Science, 2006, 7(5), 407-420
    PMID: 17073693    
     
    Virtual screening by molecular docking has become established as a method for drug lead discovery and optimization. All docking algorithms make use of a scoring function in combination with a method of search. Two theoretical aspects of scoring function performance dominate operational performance. The first is the degree to which a scoring function has a global extremum within the ligand pose landscape at the proper location. The second is the degree to which the magnitude of the function at the extremum is accurate. Presuming adequate search strategies, a scoring function's location performance will dominate behavior with respect to docking accuracy: the degree to which a predicted pose of a ligand matches experimental observation. A scoring function's magnitude performance will dominate behavior with respect to screening utility: enrichment of true ligands over non-ligands. Magnitude estimation also controls pure scoring accuracy: the degree to which bona fide ligands of a particular protein may be correctly ranked. Approaches to the development of scoring functions have varied widely, with a number of functions yielding similarly high levels of performance relating to the location issue. However, even among functions performing equally well on location, widely varying performance is observed on the question of magnitude. In many cases, performance is good enough to yield high enrichments of true ligands versus non-ligands in screening across a wide variety of protein types. Generally, performance is not good enough to correctly rank among true ligands. Strategies for improvement are discussed.

  • Protein-ligand docking: current status and future challenges.
    Sousa, Sérgio Filipe and Fernandes, Pedro Alexandrino and Ramos, Maria Jo{\~a}o
    Proteins, 2006, 65(1), 15-26
    PMID: 16862531     doi: 10.1002/prot.21082
     
    Understanding the ruling principles whereby protein receptors recognize, interact, and associate with molecular substrates and inhibitors is of paramount importance in drug discovery efforts. Protein-ligand docking aims to predict and rank the structure(s) arising from the association between a given ligand and a target protein of known 3D structure. Despite the breathtaking advances in the field over the last decades and the widespread application of docking methods, several downsides still exist. In particular, protein flexibility-a critical aspect for a thorough understanding of the principles that guide ligand binding in proteins-is a major hurdle in current protein-ligand docking efforts that needs to be more efficiently accounted for. In this review the key concepts of protein-ligand docking methods are outlined, with major emphasis being given to the general strengths and weaknesses that presently characterize this methodology. Despite the size of the field, the principal types of search algorithms and scoring functions are reviewed and the most popular docking tools are briefly depicted. Recent advances that aim to address some of the traditional limitations associated with molecular docking are also described. A selection of hand-picked examples is used to illustrate these features.

  • Prediction of Protein−Ligand Interactions. Docking and Scoring: Successes and Gaps
    Leach, Andrew R and Shoichet, Brian K and Peishoff, Catherine E
    Journal of medicinal chemistry, 2006, 49(20), 5851-5855
    doi: 10.1021/jm060999m
     
    Computational methods have become standard in today's medicinal chemistry tool kit. Like any tool, it is important to periodically evaluate utility and ask how function can be improved. In this section of the Journal, we call attention to the area of calculating molecular interactions, specifically docking, the positioning of a ligand in a protein binding site, and scoring, the quality assessment of docked ligands. As several recent reviews have made clear,1-3 the technology has been productive for both finding and elaborating bioactive molecules. But has docking and scoring delivered on the promises first made over 20 years ago? To consider that question, we follow up on an extensive symposium held in Philadelphia during the 2004 Fall National Meeting of the American Chemistry Society and on subsequent meetings sponsored by the National Institutes of Health (NIH) and the National Institute of Standards and Technology (NIST) in 2005 and 2006 to address the outcomes of the American Chemical Society symposium. Speakers at the symposium were invited to contribute original manuscripts to be published with this overview to highlight the area of docking and scoring and to identify some of the major gaps yet to be addressed.

  • Prediction of Protein−Ligand Interactions. Docking and Scoring: Successes and Gaps
    Leach, Andrew R and Shoichet, Brian K and Peishoff, Catherine E
    Journal of medicinal chemistry, 2006, 49(20), 5851-5855
    doi: 10.1021/jm060999m
     
    Computational methods have become standard in today's medicinal chemistry tool kit. Like any tool, it is important to periodically evaluate utility and ask how function can be improved. In this section of the Journal, we call attention to the area of calculating molecular interactions, specifically docking, the positioning of a ligand in a protein binding site, and scoring, the quality assessment of docked ligands. As several recent reviews have made clear,1-3 the technology has been productive for both finding and elaborating bioactive molecules. But has docking and scoring delivered on the promises first made over 20 years ago? To consider that question, we follow up on an extensive symposium held in Philadelphia during the 2004 Fall National Meeting of the American Chemistry Society and on subsequent meetings sponsored by the National Institutes of Health (NIH) and the National Institute of Standards and Technology (NIST) in 2005 and 2006 to address the outcomes of the American Chemical Society symposium. Speakers at the symposium were invited to contribute original manuscripts to be published with this overview to highlight the area of docking and scoring and to identify some of the major gaps yet to be addressed.

2004

  • Docking and scoring in virtual screening for drug discovery: methods and applications.
    Kitchen, Douglas B and Decornez, Hélène and Furr, John R and Bajorath, Jürgen
    Nature reviews. Drug discovery, 2004, 3(11), 935-949
    PMID: 15520816     doi: 10.1038/nrd1549
     
    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.

2003

  • Molecular recognition and docking algorithms.
    Brooijmans, Natasja and Kuntz, Irwin D
    Annual review of biophysics and biomolecular structure, 2003, 32, 335-373
    PMID: 12574069     doi: 10.1146/annurev.biophys.32.110601.142532
     
    Molecular docking is an invaluable tool in modern drug discovery. This review focuses on methodological developments relevant to the field of molecular docking. The forces important in molecular recognition are reviewed and followed by a discussion of how different scoring functions account for these forces. More recent applications of computational chemistry tools involve library design and database screening. Last, we summarize several critical methodological issues that must be addressed in future developments.

  • Ligand binding: functional site location, similarity and docking
    Campbell, S J and Gold, N D and Jackson, R M
    Current opinion in\ldots}, 2003, 13, 389-395
     
    ... Similarly, the evidence is that structural (or feature) similarity in the binding sites of proteins will ... The possibility that protein docking methods can also be used for site detection and ... tools for the functional characterisation of ligand-binding sites and for structure- based drug design ...

  • Ligand binding: functional site location, similarity and docking
    Campbell, S J and Gold, N D and Jackson, R M
    Current opinion in\ldots}, 2003, 13, 389-395
     
    ... Similarly, the evidence is that structural (or feature) similarity in the binding sites of proteins will ... The possibility that protein docking methods can also be used for site detection and ... tools for the functional characterisation of ligand-binding sites and for structure- based drug design ...

2002

  • Virtual screening and fast automated docking methods
    Schneider, Gisbert and Böhm, Hans-Joachim
    Drug discovery today, 2002, 7(1), 64-70
    doi: 10.1016/S1359-6446(01)02091-8
     
    ... molecules which were identified, optimized or designed using virtual screening methods a. Molecular structure, Activity, Method, Refs. Ca 2+ antagonist (T-channel blocker), Pharmacophore similarity searching, [51]. K + channel (kv 1.5) blocker, Fragment based evolutionary de novo ...

  • Virtual screening and fast automated docking methods
    Schneider, Gisbert and Böhm, Hans-Joachim
    Drug discovery today, 2002, 7(1), 64-70
    doi: 10.1016/S1359-6446(01)02091-8
     
    ... molecules which were identified, optimized or designed using virtual screening methods a. Molecular structure, Activity, Method, Refs. Ca 2+ antagonist (T-channel blocker), Pharmacophore similarity searching, [51]. K + channel (kv 1.5) blocker, Fragment based evolutionary de novo ...

  • Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors.
    Gohlke, Holger and Klebe, Gerhard
    Angewandte Chemie (International ed. in English), 2002, 41(15), 2644-2676
    PMID: 12203463     doi: 10.1002/1521-3773(20020802)41:15<2644::AID-ANIE2644>3.0.CO;2-O
     
    The influence of a xenobiotic compound on an organism is usually summarized by the expression biological activity. If a controlled, therapeutically relevant, and regulatory action is observed the compound has potential as a drug, otherwise its toxicity on the biological system is of interest. However, what do we understand by the biological activity? In principle, the overall effect on an organism has to be considered. However, because of the complexity of the interrelated processes involved, as a simplification primarily the "main action" on the organism is taken into consideration. On the molecular level, biological activity corresponds to the binding of a (low-molecular weight) compound to a macromolecular receptor, usually a protein. Enzymatic reactions or signal-transduction cascades are thereby influenced with respect to their function for the organism. We regard this binding as a process under equilibrium conditions; thus, binding can be described as an association or dissociation process. Accordingly, biological activity is expressed as the affinity of both partners for each other, as a thermodynamic equilibrium quantity. How well do we understand these terms and how well are they theoretically predictable today? The holy grail of rational drug design is the prediction of the biological activity of a compound. The processes involving ligand binding are extremely complicated, both ligand and protein are flexible molecules, and the energy inventory between the bound and unbound states must be considered in aqueous solution. How sophisticated and reliable are our experimental approaches to obtaining the necessary insight? The present review summarizes our current understanding of the binding affinity of a small-molecule ligand to a protein. Both theoretical and empirical approaches for predicting binding affinity, starting from the three-dimensional structure of a protein-ligand complex, will be described and compared. Experimental methods, primarily microcalorimetry, will be discussed. As a perspective, our own knowledge-based approach towards affinity prediction and experimental data on factorizing binding contributions to protein-ligand binding will be presented.

  • A review of protein-small molecule docking methods.
    Taylor, R D and Jewsbury, P J and Essex, J W
    Journal of computer-aided molecular design, 2002, 16(3), 151-166
    PMID: 12363215    
     
    The binding of small molecule ligands to large protein targets is central to numerous biological processes. The accurate prediction of the binding modes between the ligand and protein, (the docking problem) is of fundamental importance in modern structure-based drug design. An overview of current docking techniques is presented with a description of applications including single docking experiments and the virtual screening of databases.