title: A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds.
abstract: Allosteric inhibition of coagulation enzymes offers the advantage of controlled inhibition. In this study, a small library of mono sulfated indole and benzothiazole based molecules was synthesized and screened against the panel of coagulation proteases. The results reveal that selected molecules inhibit the thrombin, factor Xa and factor XIa with moderate potency. Compound 6a was found to have an allosteric mode of inhibition against thrombin. Plasma clotting assays suggest that selected inhibitors 14b, 14c and 14d prolong both prothrombin and activated partial thromboplastin time. Overall, this work presents the newer class of allosteric inhibitors of thrombin and factor XIa with improved aqueous solubility profile.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States; Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, United States. Electronic address: preetpalsidhu@gmail.com.
authors.forename: Preetpal Singh
authors.initials: PS
authors.lastname: Sidhu
authors.affiliation: Institute for Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hunan 430074, PR China.
authors.forename: Qibing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States; Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, United States.
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000494:Allosteric Regulation; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry*; D001777:Blood Coagulation / Q000187:drug effects*; D015195:Drug Design; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D015951:Factor Xa / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D052160:Benzothiazoles; D015945:Factor XIa; D013917:Thrombin; D015951:Factor Xa; C005465:benzothiazole
keywords: Anticoagulation; Factor XIa; Sulfation; Thrombin