Tadalafil (Cialis): A Patient Case Related to Tadalafil and its Interaction with Phosphodiesterase 5
This Jmol Exploration was created using the Jmol Exploration Webpage Creator from the MSOE Center for BioMolecular Modeling.
Erectile dysfunction (ED), or impotence, is defined as 'the inability to achieve and/or maintain a penile erection sufficient for sexual performance.'1 Prevalence of erectile dysfunction is increased in middle aged and older men and is often associated with other age-related conditions including hypertension, diabetes mellitus, peripheral vascular disease, and hypercholesterolemia.1,2
A 58 year old male was admitted to Meriter Hospital in Madison, WI, to be treated for a bacterial infection.Past medical history of the patient included diabetes mellitus, hypertension, hypercholesterolemia, erectile dysfunction, and angina. The patient was prescribed tadalafil (Cialis) 10mg as needed for ED, as well as nitroglycerin 0.4mg sublingual tablets as needed for angina. The pharmacist went to the patient's room to confirm that he was not taking these medications concurrently, as this could lead to severe hypotension, syncope, and angina. The pharmacist stressed the importance of not taking these medications within a 48-hour time period to avoid these serious drug-drug interactions.
Please click on the button below to view the 3D image of Cialis.
View 3D CialisPharmacologic treatment of ED has been developed to target and inhibit the PDE-5 enzyme. The molecular formula and pharmacokinetic properties of tadalafil is C22H19N3O4, with a molecular weight of 389.404 Da. Tadalafil has a volume of distribution of 63 liters and protein binding of 94%. The maximum plasma concentration is achieved between 30 minutes and 6 hours, with a half-life of 17.5 hours. Tadalafil is primarily metabolized by CYP3A4.6
'Phosphodiesterase type 5 inhibitors are considered to be the first-line therapy for the treatment of erectile dysfunction.'3 These drugs work to enhance the effects of NO on the corpus cavernosum of the penis by inhibiting the PDE-5 enzyme from degrading the second messenger, cGMP.7 By preventing the degradation of cGMP, tadalafil allows for the patient to have a better ability to achieve and maintain an erection needed for sexual activity.
Phosphodiesterases (PDEs) are a superfamily of proteins that degrade cAMP and cGMP and are essential regulators of nucleotide signaling, having many physiological functions and serving as significant drug targets. Of the 12 PDE families, cGMP-specific PDE-5 exists as a protein dimer and is the principle cGMP hydrolyzing enzyme in the corpus cavernosum tissue. This is the specific target of the drug, tadalafil.4 Tadalafil is a competitive antagonist which shares an active site with cGMP.
View protein dimer without drug boundWithin a subunit of the PDE-5 protein dimer is an active site where cGMP normally binds. This is where tadalafil will competitively inhibit cGMP. Click below to zoom into the active site.
Zoom into active siteTadalafil binds to PDE-5 with a Kd range of 0.9-6.7 nM, approximately 200-700 times more tightly than it binds to PDE-6, showing its increased specificity for this enzyme. 'PDE-5 is composed of an amino-terminal regulatory domain and a carboxy-terminal metal binding, catalytic domain.'4 The catalytic domain contains a core of 16 alpha-helices and three subdomains: an N-terminal cyclin-fold region, a linker region, and a C-terminal helical bundle.4,8 The active site is found within the catalytic domain.
The button below will show the secondary structure of one dimer of the protein PDE-5, with the drug visible in the active site.
Below shows the secondary structures of PDE-5. There are 16 alpha helices and no visible beta sheets.
View alpha helices of PDE-5The active site of PDE-5 is located at the center of the C-terminal helical bundle domain. The substrate pocket is approximately 10 angstroms deep with a narrow opening and a wide inner space; it forms a deep, hydrophobic pocket.4,8 It is composed of four subsites: a metal-binding domain (M site), a core pocket (Q pocket), a hydrophobic pocket (H pocket), and a lid region (L region). Tadalafil shows no significant interactions with the M site or L region of the protein and interacts most significantly with the Q and H pockets.
The Q pocket is composed of the following amino acids:
Alanine (ala)- shown in orange
Tyrosine (tyr)- purple
Glutamine (gln)- teal
Methionine (met)- green
Serine (ser)- yellow
Tadalfil binds closely in the active site and is almost completely surrounded by the interacting amino acid side chains. The button below shows tadalafil bound with the amino acids of the active site.
View drug interacting with amino acid residuesThe Q pocket side chain of Gln (shown in teal) forms a single hydrogen bond with the NH group of the indole ring of tadalafil. The hydrogen bond is highlighted in red.
View hydrogen bondThe H pocket is responsible for hydrophobic interacitons with the methylene-dioxyphenyl group of tadalafil, which may be one of the reasons why tadalafil maintains high affinity with PDE-5. Each color represents a different amino acid that contributes to forming the H pocket.
View hydrophobic pocketThe PDE-5 enzyme is necessary for the breakdown of the secondary messenger, cGMP. Tadalafil has the ability to inhibit PDE-5 allowing for prolonged smooth muscle relaxation in the penile corpus cavernosum and leading to an erection. This can be extremely beneficial for men suffering from ED but can also be dangerous for patients simultaneously taking organic nitrate vasodilators, such as nitroglycerin.
The patient was prescribed tadalafil 10mg as needed for ED and nitroglycerin 0.4mg sublingual as needed for angina. Together, this combination of drugs puts him at an increased risk of developing extreme hypotension, syncope, angina, or even death. This risk is due, in part, to two major factors: the presence of PDE-5 receptors in various cells and the synergistic, pharmacodynamic effect of these two drugs.
1. Curran MP, Keating GM. Tadalafil. Drugs. 2003; 63 (20): 2203-2212.
2. Meller SM, Stilp E, Walker CN, Mena-Hurtado C. The link between vasculogenic erectile dysfunction, coronary artery disease, and peripheral artery disease: role of metabolic factors and endovascular therapy. J Invasive Cardiol. 2013 June; 25 (6): 313-319.
3. McVary KT. Clinical practice: erectile dysfunction. N Engl J Med. 2007 Dec; 357 (24): 2472-2481.
4. Sung B, Hwang KY, Jeon YH, Lee JI, Heo Y, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park S, Lee J, Lee TG, Ro S, Cho JM. Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature. 2003 Sep; 425.
5. Padma-Nathan H. Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. Am J Cardiol. 2003 Nov; 92 (9A): 19M-25M.
6. Tadalafil: DB00820. DrugBank: open data drug & drug target database (updated Feb 8, 2013). Retrieved from: http://www.drugbank.ca/drugs/DB00820. Accessed Dec 5, 2013.
7. Tadalafil. Lexi-Comp Online, Lexi-Drugs Online, Hudson, OH: Lexi-Comp, Inc.; Accessed Nov 16, 2013.
8. Dalby K. Phosphodiesterase inhibitors. In Lemke TL, Williams DA, Roche VF, Zito SW (Eds.), Foye''s principles of medicinal chemistry, 6th edition (pp.480-488). Philadelphia, PA: Lippincott Williams & Wilkins; 2008.