Beware of docking! Trends in Pharmacological Sciences Yu-Chian Chen  Trends in Pharmacological Sciences  Volume 36, Issue 2, Pages 78-95 (February 2015) DOI: 10.1016/j.tips.2014.12.001 Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 1 The increase in the number of papers, from 1990 to 2013, retrieved from the PubMed Central (PMC)-NCBI database (http://www.ncbi.nlm.nih.gov/pmc/). Keywords were ‘docking’ or ‘dock’ shown in the abstract or title. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 2 All docking publications from 1990 to 2013. Autodock, GOLD, and Glide are the most-used docking programs. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 3 Flow chart of the docking procedure. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 4 The docking mode can be roughly divided into four types of docking mode. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 5 The ligand, angeliferula, is docked well into the binding site of protein phosphatase 2A (PP2A), and with the highest dock score. There is a clear difference between the docking pose and the final ligand pose after a molecular dynamics (MD) simulation of 20ns [183]. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 6 The ligand, dichotomoside E, is docked well into the binding site of protein phosphatase 2A (PP2A), and has the highest dock score. There is also a clear difference between the docking pose and the final ligand pose after a molecular dynamics (MD) simulation of 20ns [183]. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 7 The ligand, FOG1, is docked well into the binding site of retinoblastoma-associated protein (RbAp48), and with the highest dock score. Again, there is a clear difference between the docking pose and the final ligand pose after a molecular dynamics (MD) simulation of 20ns [184]. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 8 The ligand, ningposides C, is docked well into the binding site of histone deacetylase 2 (HDAC2), and with the highest dock score. As before, there is a major difference between docking pose and the final ligand pose after a molecular dynamics (MD) simulation of 20ns [181]. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 9 Flowchart of computer-aided drug design (CADD). The protocol is divided into three parts: structure-based drug design, ligand-based drug design, and validation by molecular dynamics simulation. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 10 The possible four modes for drug design in silico. Case (A) shows a ligand with rapid docking in the binding site and also a long residence time in molecular dynamics (MD) simulation. Thus, it might exhibit superiority as a potent lead. In case (B) the ligand has a lower dock score but a long residence time. In (C) it shows rapid binding with a high dock score but with a short residence time. The total occupation time is short; however, this might not be disadvantageous because the ligand can bind again quickly. Theoretically, case (D) is not a good candidate because it shows a lower docking speed and short residence time. Trends in Pharmacological Sciences 2015 36, 78-95DOI: (10.1016/j.tips.2014.12.001) Copyright © 2014 Elsevier Ltd Terms and Conditions