1,721,130 research outputs found
Targeting the Eph-ephrin system with protein-protein interaction (PPI) inhibitors
No full textEph-ephrin system is emerging as a new potential target in several diseases including cancer, diabetes, neurodegenerative diseases and inflammation. In the last decade, several efforts have been made to develop small molecule antagonists of Eph receptors. Both natural and synthetic compounds were discovered with (poly) phenol and steroidal derivatives on one side and the α1 agonist doxazosin, 2,5-dimethylpyrrol- 1-yl-benzoic acids and amino acid conjugates of lithocholic acid on the other. In the present paper we critically present available data for these compounds and discuss their potential usefulness as pharmacological tools or as candidates for a lead-optimization program
Computational enzymology
No full textTechniques for modelling enzyme-catalyzed reaction mechanisms are making increasingly important contributions to biochemistry. They can address fundamental questions in enzyme catalysis and have the potential to contribute to practical applications such as drug development
On the Use of 2,5-Dimethyl-Pyrrol-1-yl-Benzoic Acid Derivatives as EPH-Ephrin Antagonists.
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The Increasing Role of QM/MM in Drug Discovery
No full textSince its first appearance in 1976, the quantum mechanics/molecular mechanics (QM/MM) approach has mostly been used to study the chemical reactions of enzymes, which are frequently the target of drug discovery programs. In principle, a detailed understanding of the enzymatic mechanism should help researchers to design a potent enzyme inhibitor or new drug. However, QM/MM has not yet had a widespread impact on structure-based drug design. This is mostly due to its high computational cost. We expect this to change with the recent and extraordinary increases in computational power, and with the availability of more efficient algorithms for QM/MM calculations. Here, we report on some representative examples of QM/MM studies, including our own research, of pharmaceutically relevant enzymes, such as ribonuclease H and fatty acid amide hydrolase (FAAH). We aim to show how QM/MM has traditionally been used to study enzymatic catalysis. In this regard, we discuss its potential to become a routinely used drug design tool. To support this, we also discuss selected computational studies where QM/MM insights have been helpful in improving the potency of covalent inhibitors of FAAH
Fatty acid amide hydrolase inhibitors: a patent review (2009 - 2014)
Full text linkIntroduction: Fatty acid amide hydrolase (FAAH) is a key enzyme responsible for the degradation of the endocannabinoid anandamide. FAAH inactivation is emerging as a strategy to treat several CNS and peripheral diseases, including inflammation and pain. The search for effective FAAH inhibitors has thus become a key focus in present drug discovery.
Areas covered: Patents and patent applications published from 2009 to 2014 in which novel chemical classes are claimed to inhibit FAAH.
Expert opinion: FAAH is a promising target for treating many disease conditions including pain, inflammation and mood disorders. In the last few years, remarkable efforts have been made to develop new FAAH inhibitors (either reversible and irreversible) characterized by excellent potency and selectivity, to complete the arsenal of tools for modulating FAAH activity. The failure of PF-04457845 in a Phase II study on osteoarthritis pain has not flattened the interest in FAAH inhibitors. New clinical trials on ‘classical’ FAAH inhibitors are now ongoing, and new strategies based on compounds with peculiar in vivo distribution (e.g., peripheral) or with multiple pharmacological activities (e.g., FAAH and COX) are under investigation and could boost the therapeutic potential of this class in the next future
Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.
No full textFAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target
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