High-Throughput Docking and Molecular Dynamics Simulations towards the Identification of Potential Inhibitors against Human Coagulation Factor XIIa

Abstract

Human coagulation factor XIIa (FXIIa) is a trypsin-like serine protease that is involved in pathologic thrombosis. As a potential target for designing safe anticoagulants, FXIIa has received a great deal of interest in recent years. In the present study, we employed virtual high-throughput screening of 500,064 compounds within Enamine database to acquire the most potential inhibitors of FXIIa. Subsequently, 18 compounds with significant binding energy (from -65.195 to -15.726 kcal/mol) were selected, and their ADMET properties were predicted to select representative inhibitors. Three compounds (Z1225120358, Z432246974, and Z146790068) exhibited excellent binding affinity and druggability. MD simulation for FXIIa-ligand complexes was carried out to reveal the stability and inhibition mechanism of these three compounds. Through the inhibition of activated factor XIIa assay, we tested the activity of five compounds Z1225120358, Z432246974, Z45287215, Z30974175, and Z146790068, with pIC50 values of 9.3∗10−7, 3.0∗10−5, 7.8∗10−7, 8.7∗10−7, and 1.3∗10−6 M, respectively; the AMDET properties of Z45287215 and Z30974175 show not well but have better inhibition activity. We also found that compounds Z1225120358, Z45287215, Z30974175, and Z146790068 could be more inhibition of FXIIa than Z432246974. Collectively, compounds Z1225120358, Z45287215, Z30974175, and Z146790068 were anticipated to be promising drug candidates for inhibition of FXIIa.

Computational Approach for Covalent Lead Identification against Spike Glycoprotein of SARS-CoV-2

“…Metabolism parameter involves parameters of cytochrome P450 inhibitors which affect the drug metabolism were also considered for the screening. Excretion parameter like renal clearance was also included along with non-toxicity through LD50 value, non-hepatoxicity and non-mutagenicity were also included as criteria for selecting the compounds [38] . The compounds ful lling mainly nontoxicity and non-mutagenicity criteria were considered further for virtual screening and docking studies.…”

“…Thus, spike protein is a classic target for drug development. Coutard et al proposed an inhibitor nding for furin because the sequence of S protein has particular furin-like cleavage [38] . This present study, which predicts the inhibition of top 5 screened organic covalent compounds against S protein, has disclosed different results indicating that 3-ethyl-5propyladamantan-1-amine have better binding pose other compounds.…”

COVID-19 and the Kidney: Should Nephrologists Care about COVID-19 rather than Maintaining Their Focus on Renal Patients?

“…Indeed, emerging evidence suggests that the human kidney is a specific target of SARS-CoV-2 that may have a direct effect on kidney cells [ 72 , 73 , 74 , 75 ]. Tubular epithelial cells and podocytes exhibit high levels of ACE2 and TMPRSS2, indicating that they are possible SARS-CoV-2 targets [ 76 , 77 ]. ACE2 internalization following SARS-CoV-2 infection could influence an imbalance in the renin-angiotensin-aldosterone system, with increased angiotensin II (Ang II) signaling leading to proinflammatory and fibrotic processes in the kidney [ 78 , 79 ].…”

New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation

“…Compounds targeting nearly every enzyme in the blood coagulation cascade are being developed to identify new anticoagulants that are at least as effective as existing drugs and without the risk of bleeding complications. Among them, factor XIIa or factor XIa are promising targets for creating drugs based on their inhibitors, since a deficiency of these factors protects against thrombosis without causing spontaneous bleeding [1][2][3][4].…”

“…TF and factor VIIa constitute a tenase complex which catalyzes the activation of factor X and, because of further sequential activation of coagulation factors, also leads to clot formation. Thus, the position of coagulation factor XIIa in the cascade of biochemical reactions will make it possible to create, on the basis of its inhibitors, a new class of anticoagulants capable of blocking the internal pathway of coagulation activation, while not disrupting the chain of reactions of plasma hemostasis activated by the external pathway [1][2][3][4].…”