Recent Advances in Molecular Docking for the Research and Discovery of Potential Marine Drugs

Abstract

Marine drugs have long been used and exhibit unique advantages in clinical practices. Among the marine drugs that have been approved by the Food and Drug Administration (FDA), the protein-ligand interactions, such as cytarabine-DNA polymerase, vidarabine-adenylyl cyclase, and eribulin-tubulin complexes, are the important mechanisms of action for their efficacy. However, the complex and multi-targeted components in marine medicinal resources, their bio-active chemical basis, and mechanisms of action have posed huge challenges in the discovery and development of marine drugs so far, which need to be systematically investigated in-depth. Molecular docking could effectively predict the binding mode and binding energy of the protein-ligand complexes and has become a major method of computer-aided drug design (CADD), hence this powerful tool has been widely used in many aspects of the research on marine drugs. This review introduces the basic principles and software of the molecular docking and further summarizes the applications of this method in marine drug discovery and design, including the early virtual screening in the drug discovery stage, drug target discovery, potential mechanisms of action, and the prediction of drug metabolism. In addition, this review would also discuss and prospect the problems of molecular docking, in order to provide more theoretical basis for clinical practices and new marine drug research and development.

Keywords: marine drugs; mechanism of action; molecular docking; protein–ligand interaction; target protein.

Figure 1

Chemical structures of the 12 approved marine drugs of anticancer (a), antibacterial (b), analgesic (c), cardiovascular (d), and antiviral (e) agents [3,8]. BS: biological source. Abbreviations of amino acids: A, Alanine; C, Cysteine; D, Aspartic acid; G, Glycine; K, Lysine; L, Leucine; M, Methionine; R, Arginine; S, Serine; T, Threonine; Y, Tyrosine. FDA, Food and Drug Administration (USA); EMEA, European Medicines Evaluation Agency; AEMPS, Agencia Española de Medicamentos y Productos Sanitarios (Spain); HC, Health Canada; ISS, Istituto Superiore di Sanità (Italy); PMDA, Pharmaceuticals and Medical Devices Agency (Japan).

Figure 2

The docking types of Lock–Key Model (a) and Induced Fit Theory (b).

Figure 3

The interaction interfaces of the protein–ligand complexes. The ligand (red) represents the protein (a) or small molecule (b), respectively. The protein (receptor) is green.

Figure 4

Structures of three halogenated compounds isolated from marine algae Symphyocladia latiuscula. Abbreviations: 2,3-DA, 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol; 2,3-ME, 2,3,6-tribromo-4,5- dihydroxybenzyl methyl ether; bis-2,3-DE, bis-(2,3,6-tribromo-4,5-dihydroxybenzyl)ether.

Figure 5

Potential compounds isolated from the seaweeds of Dictyopteris hoytii.

Figure 6

Two sulfated sterol derivatives (solomonsterols A, B) isolated from Theonella swinhoei.

Figure 7

Two polyether derivatives (compounds 1, 2) isolated from the thalli of Gracilaria salicornia.

Figure 8

Chemical structures of metabolites 1–8 isolated from the soft coral Sarcophyton ehrenbergi.

Figure 9

Structures of the small molecule compounds isolated from the marine sponge Xestospongia exigua (Araguspongine C) and the octocoral Plexaura homomalla (Prostaglandin A₂ and Prostaglandin A₂-AcMe), respectively.