Molecular modeling optimization of anticoagulant pyridine derivatives

Abstract

Intravascular clotting remains a major health problem in the United States, the most prominent being deep vein thrombosis, pulmonary embolism and thromboembolic stroke. Previous reports on the use of pyridine derivatives in cardiovascular drug development encourage us to pursue new types of compounds based on a pyridine scaffold. Eleven pyridine derivatives (oximes, semicarbazones, N-oxides) previously synthesized in our laboratories were tested as anticoagulants on pooled normal plasma using the prothrombin time (PT) protocol. The best anticoagulant within the oxime series was compound AF4, within the oxime N-oxide series was compound AF4-N-Oxide, and within the semicarbazone series, compound MD1-30Y. We also used a molecular modeling approach to guide our efforts, and found that there was good correlation between coagulation data and computational energy scores. Molecular docking was performed to target the active site of thrombin with the DOCK v5.2 package. The results of molecular modeling indicate that improvement in anticoagulant activities can be expected by functionalization at the 3-position of the pyridine ring and by N-oxide formation. Results reported here prove the suitability of DOCK in the lead optimization process.

Evaluation of biological activity of some pyridine derivatives on perfusion pressure and their interaction with the M2 muscarinic receptor

“…Analyzing the hypothesis above mentioned and other reports which indicate that some pyridine derivatives produce changes in the perfusion pressure [13,14] through M2 muscarinic receptor activation. [15,16,[41][42][43] For this reason, in this research a theoretical evaluation on interaction of compounds 6, 9 and 13 with M2 muscarinic receptor was determinate.…”

An in-Silico Study of Some Natural and Synthetic Compounds as Potential Inhibitors for Factor Xa

“…Therefore, the coagulation process is a complex cascade of enzymatic reactions that can be activated via both intrinsic and extrinsic pathways 7 . The final step in coagulation is the formation of the fibrin clot from fibrinogen, by the action of thrombin, which acts as a serine protease, which is generated by prothrombin through factor Xa 8 . Therefore, factor X is considered the connecting point between the coagulation cascades.…”