In silico design of a dual TPR/TxS inhibitor for venous thromboembolism and related cardiovascular diseases

Abstract

In recent years, many research efforts have been directed towards preventing vasoconstrictor and platelet aggregatory properties of TxA2 related to the prostaglandin cycle, as TxA2 has been implicated directly or indirectly in pathologies such as cardiovascular diseases, venous thromboembolism, and pulmonary embolism. The TxA2 antagonists and TxS inhibitors undergoing clinical trials have not shown the expected clinical efficacy. This molecular modeling and docking study explains how efficacy may be enhanced by a careful design of multitarget drugs producing synergistic effects simultaneously at different targets. A dual TPR/TxS inhibition strategy is expected to give better clinical efficacy. This study also emphasizes the importance of designing efforts based on detailed analysis of drug−receptor interactions at both targets. Ab initio HF/6-31G(d) and B3LYP/6-31G(d) molecular orbital calculations coupled with flexible ligand docking studies have led to the design of a dual TPR/TxS inhibitor starting from a naturally occurring compound bromelain, derived from pineapple extract with some known pharmacological advantages. A designed lead compound may prove to be a fruitful starting point for the development of clinically efficient drugs for venous thromboembolism and related cardiovascular diseases.