Discovery of Multitarget Inhibitors by Combining Molecular Docking with Common Pharmacophore Matching

Abstract

Multitarget drugs have been to be found effective in controlling complex diseases. However, how to design multitarget drugs presents a great challenge. We have developed a computer-assisted strategy to screen for multitarget inhibitors using a combination of molecular docking and common pharmacophore matching. This strategy was successfully applied to screen for dual-target inhibitors against both the human leukotriene A(4) hydrolase (LTA4H-h) and the human nonpancreatic secretory phospholipase A2 (hnps-PLA2). Three compounds screened from the chemical database MDL Available Chemical Directory were found to inhibit these two enzymes at the 10 microM level. Moreover, one synthetic compound matching the common pharmacophores inhibits LTA4H-h and hnps-PLA2 with IC(50) values of 35 nM and 7.3 microM, respectively. The common pharmacophore model can also be used to search small molecule databases or collections of existing inhibitors, as well as to guide combinatorial library design to search for ideal multitarget inhibitors.

Insights into binding modes of adenosine A2B antagonists with ligand-based and receptor-based methods

“…If ligand-based and receptor-based methods were used together, they may be complementary each other and provided more useful information. For example, molecular docking in combination with pharmacophore searches had been successfully used to identify novel ligands through virtual screening [48,49]. In this study, we combined pharmacophore model, homology model and molecular docking together to create a consensus predictive model, which could predict the potency of A 2B antagonists and provide new insights into the binding modes of A 2B antagonists.…”

Computational Methods in Drug Discovery

“…Multitarget Inhibitors Using Common Pharmacophore Models. Wei et al (2008) used Pocket v.2 to identify a common pharmacophore for two targets involved in inflammatory signaling, human leukotriene A4 hydrolase (LTA4H-h) and human nonpancreatic secretory phospholipase A 2 (PLA 2 ). The cocrystal structure (PDB code 1HS6) of LTA4H-h with 2-(3-amino-2-hydroxy-4-phenylbutyrylamino)-4-methylpentanoic acid (bestatin) and the structure (PDB code 1DB4) of PLA 2 with [3-(1-benzyl-3-carbamoylmethyl-2-methyl-1H-indol-5-yloxy)propyl]phosphonic acid (indole 8) were used to derive pharmacophores of the two targets.…”

In-Silico Approaches to Multi-target Drug Discovery

“…To improve virtual screening performance, molecular dynamics-enhanced molecular docking method has been used in virtual screening against the individual targets in HIV and its associated opportunistic pathogens to find multi-target agents, such as KNI-764, that inhibit both HIV-1 protease and malarial plasmepsin II enzyme (40). Molecular docking and pharmacophore matching methods have been used for identifying dual-inhibitors of two antiinflammatory targets, PLA2 and LTA4H-h, in the arachidonic acid metabolic network (41).…”