title: Interactions of some commonly used drugs with human α-thrombin.
abstract: Adverse side effects of drugs are often caused by the interaction of drug molecules to targets other than the intended ones. In this study, we investigated the off-target interactions of some commercially available drugs with human α-thrombin. The drugs used in the study were selected from Super Drug Database based on the structural similarity to a known thrombin inhibitor argatroban. Interactions of these drugs with thrombin were initially checked by in silico docking studies and then confirmed by thrombin inhibition assay using a fluorescence microplate-based method. Results show that the three commonly used drugs piperacillin (anti-bacterial), azlocillin (anti-bacterial), and metolazone (anti-hypertensive and diuretic) have thrombin inhibitory activity almost similar to that of argatroban. The Ki values of piperacillin, azlocillin, and metolazone with thrombin are .55, .95, and .62 nM, respectively. The IC50 values of piperacillin, azlocillin, and metolazone with thrombin are 1.7, 2.9, and 1.92 nM, respectively. This thrombin inhibitory activity might be a reason for the observed side effects of these drugs related to blood coagulation and other thrombin activities. Furthermore, these compounds (drugs) may be used as anti-coagulants as such or with structural modifications.
authors.affiliation: a Department of Biotechnology and Microbiology , Kannur University , Thalassery Campus, Palayad P.O., Kannur , Kerala 670661 , India.
authors.forename: Divya Gopalakrishnan
authors.initials: DG
authors.lastname: Nair
authors.forename: Sunilkumar Puthenpurackal
authors.initials: SP
authors.lastname: Narayanan
authors.forename: Sadasivan
authors.initials: S
authors.lastname: Chittalakkottu
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives; D001390:Azlocillin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008788:Metolazone / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000737:chemistry* / Q000378:metabolism; D010878:Piperacillin / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013449:Sulfonamides; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; D001390:Azlocillin; C031942:argatroban; D008788:Metolazone; D010878:Piperacillin
keywords: argatroban; docking; drug side effects; off-target interactions; thrombin inhibition