User:Matthew J Lowry/Sandbox 1

Function

Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion ^[1]. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis^[2]. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis ^[3]. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects^[4].

Structural Highlights

Montelukast has the chemical formula of C₃₅H₃₆ClNO₃S with a molecular weight of 586.187 Da ^[5]. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da ^[6]. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains ^[7]. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein ^[8]. Figure 1 of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.

Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da ^[9]. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets^[10]. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms^[11]. Montelukast () is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast^[12]. Residue Thr107 helps stabilize the polarity induced by the Chlorine ^[12]. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction ^[12]. The binding pocket can be three-dimensionally visualized using JSmol.

To view 2NNI colored by group click . To see a transparent view of the protein click of the protein.

Mechanism

Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory^[13]. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)^[3].

5-lipoxygenase Pathway

All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid^[14]; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) ^[15]. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 ^[15]. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.

Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor ^[14]. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance ^[15]. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it.

LTB4 Pathway

Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT ^[14].This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma ^[15]. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 ^[16].This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade ^[16].