ABSTRACT
Indoleamine 2, 3-dioxygenase 1 (IDO1) is the only rate-limiting enzyme outside the liver that catalyzes the oxidation and cracking of indole rings in the tryptophan along the kynurenine pathway (KP). The overactivation of IDO1 is closely related to the pathogenesis of various human immune and neurological diseases. As an important target for the treatment of many human serious diseases, including malignant tumors, the development of IDO1 inhibitors is of great practical significance. In this work, the structure and function of IDO1 both are summarized from the aspects of the signal pathway, catalytic mechanism, structural biology, and so on. Moreover, the current development status of IDO1 inhibitors is also systematically reviewed, which provides assistance for anti-cancer drug design based on the structure of receptors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoles/chemical synthesis , Neuroprotective Agents/chemical synthesis , Triazoles/chemical synthesis , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Depression/drug therapy , Depression/enzymology , Depression/genetics , Depression/immunology , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Gene Expression , Histocompatibility, Maternal-Fetal/genetics , Humans , Imidazoles/metabolism , Imidazoles/therapeutic use , Immune Tolerance , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoles/metabolism , Indoles/therapeutic use , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/immunology , Neuroprotective Agents/metabolism , Neuroprotective Agents/therapeutic use , Signal Transduction , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/therapeutic use , Tumor Escape/drug effectsABSTRACT
After decades of efforts, tuberculosis has been well controlled in most places. The existing drugs are no longer sufficient for the treatment of drug-resistant Mycobacterium tuberculosis due to significant toxicity and selective pressure, especially for XDR-TB. In order to accelerate the development of high-efficiency, low-toxic antituberculosis drugs, it is particularly important to use Computer Aided Drug Design (CADD) for rational drug design. Here, we systematically reviewed the specific role of molecular simulation in the discovery of new antituberculosis drugs. The purpose of this review is to overview current applications of molecular simulation methods in the discovery of antituberculosis drugs. Furthermore, the unique advantages of molecular simulation was discussed in revealing the mechanism of drug resistance. The comprehensive use of different molecular simulation methods will help reveal the mechanism of drug resistance and improve the efficiency of rational drug design. With the help of molecular simulation methods such as QM/MM method, the mechanisms of biochemical reactions catalyzed by enzymes at atomic level in Mycobacterium tuberculosis has been deeply analyzed. QSAR and virtual screening both accelerate the development of highefficiency, low-toxic potential antituberculosis drugs. Improving the accuracy of existing algorithms and developing more efficient new methods for CADD will always be a hot topic in the future. It is of great value to utilize molecular dynamics simulation to investigate complex systems that cannot be studied in experiments, especially for drug resistance of Mycobacterium tuberculosis.
