In-silico modification of antibacterial sulfa drugs to reduce affinity towards off-target Sepiapterin Reductase
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1 In-silico modification of antibacterial sulfa drugs to reduce affinity towards off-target Sepiapterin Reductase Mariya al-rashida Department of Chemistry, Forman Christian College (A Chartered University), Lahore, Pakistan
2 I m from Lahore, Pakistan!
3 Lahore is a beautiful city!
4 Badshahi Mosque, Lahore
5
6 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide
7 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide
8 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide 4-aminobenzenesulfonamide
9 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide 4-aminobenzenesulfonamide Sulfonamide group
10 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide Sulfa Drugs are sulfonamide containing drugs 4-aminobenzenesulfonamide Sulfonamide group
11 What are sulfa Drugs? Sulfa drugs are antibacterial drugs that are derivatives of 4- aminobenzenesulfonamide Sulfa Drugs are sulfonamide containing drugs But all sulfonamides are NOT sulfa drugs! 4-aminobenzenesulfonamide Sulfonamide group
12 What are sulfa Drugs? It is important to make a distinction between sulfa drugs and other sulfur-containing drugs, there are many other drugs that contain sulfur in them but they are NOT classified as sulfa drugs So what are sulfa drugs?
13
14 Sulfa drugs contain substitution at this nitrogen atom
15 Sulfamethoxazole
16 Examples of some sulfa drugs Sulfapyridine Sulfamerazine Sulfadiazine Sulfamethoxypyridazine
17 History of Sulfa Drugs Sulfonamide drugs were the first antibiotics to be used systemically, and paved the way for the antibiotic revolution in medicine. Experiments with the first sulfa drug Prontosil (which is actually a prodrug) began in 1932 It was the first and only effective antibiotic available in the years before penicillin It was the first ever medicine that could effectively treat a broad range of bacterial infections inside the body sulfa drugs continued to thrive through the early years of World War II
18 So sulfa drugs are antibacterial agents, but how do they actually exert their antibacterial effect?
19 Antibacterial Mechanism of Action of Sulfa Drugs Sulfa drugs are effective antibacterial agents since they inhibit the enzyme dihydropteroate synthetase (DHPS) DHPS (EC ) is bacterial enzyme that produces dihydropteroate in bacteria, which is required for folate production in bacteria Higher vertebrates, including humans, cannot synthesize their own folate, instead folate is a dietary requirement Hence, sulfa drugs selectively target only the bacterial enzyme DHPS
20 Diminished Use of Sulfa Drugs Why? Today, sulfa drugs are no longer the antibacterial drugs of choice, and there are a few important reasons: 1. As with any other drug, over the years, sulfa drugs have been replaced by better/newer drugs 2. Because of increased bacterial resistance against sulfa drugs, the world had to move away from them and find other alternatives 3. But arguably the Number ONE Reason is sulfa allergies! 4. Sulfa allergies are a broad spectrum set of undesired side effects that arise due to use of sulfa drugs 5. In some cases, people who have sulfa allergies may also be susceptible to developing similar allergies from other sulfonamide containing drugs
21 The molecular basis of most of the side effects of sulfa drugs remains unknown In 2013, a study by Hiruki and co-workers reported inhibition of another enzyme, sepiapterin reductase (SR) as an off-target for the sulfa drugs Based on the crystal structure of SR co-crystallized with sulfa drugs, they were able to rationalize how structurally diverse sulfa drugs might be able to target SR Haruki, H., Pedersen, M.G., Gorska, K.I., Pojer, F., Johnsson, K. Tetrahydrobiopterin biosynthesis as an offtarget of sulfa drugs (2013) Science 340:
22 Sepiapterin Reductase (SR) Sepiapterin Reductase (EC ) is an enzyme that catalyzes the NADPH-dependent reduction of pteridines and other carbonyl substances and plays a role in the biosynthesis of tetrahydrobiopterin Tetrahydrobiopterin (BH 4, also known as sapropterin), is an important co-factor that is required for normal functioning of many enzymes, such as, biopterin-dependent Aromatic Amino Acid Hydroxylases (AAAH). These AAAHs include phenylalanine 4-hydroxylase (EC ), tyrosine 3-hydroxylase (EC ), and tryptophan 5- hydroxylase (EC ), whereby phenylalanine, tyrosine, and tryptophan are respectively hydroxylated
23 Tetrahydrobiopterin also plays a key role in the biosynthesis of neurotransmitters such as serotonin, melatonin, dopamine, norepinephrine and epinephrine. Tetrahydrobiopterin acts as a co-factor for the enzyme nitric oxide synthase for the production of nitric oxide (NO) Biosynthesis of this important enzyme co-factor is started from guanosine triphosphate (GTP) and involves three enzymes, GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and finally sepiapterin reductase (SR).
24
25 So what is so bad about SR inhibition by sulfa drugs? Several neurological disorders, such as Dopa-responsive dystonia, Alzheimer's and Parkinson's disease, autism, and depression, have been suggested to be a consequence of limited tetrahydrobiopterin availability Sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis provides a rationale for some of their central nervous system related side effects, particularly in high-dose sulfamethoxazole therapy of pneumonia
26 What this study is about? In this work, we have modulated the structure of sulfa drugs, using insilico computational chemistry techniques, in attempts to reduce its binding affinity towards SR without compromising too much on its antimicrobial potential (dihydropteroate synthase (DHPS) binding potential), and in the process identify structural elements responsible for this effect
27 Modification of structural elements of sulfa drugs in this way will allow us to design better drugs that retain the benefits of excellent antimicrobial potential of sulfa drugs, while at the same time reducing the inhibition of off-target SR, hence minimizing some of the neurological side-effects notoriously associated with these outstanding antimicrobial drugs.
28 Haruki et al 2013 determined SR inhibitory potential of sulfa drugs along with other sulfonamide containing drugs. Sulfasalazine was found to be the potent inhibitor with IC 50 value of 7 nm [Haruki 2013], whereas the least active sulfa drug was sulfamethazine (IC 50 = nm), and due to its very weak inhibition it was used as a negative control We now wanted to modulate the structure of sulfasalazine (and subsequently some other sulfa drugs) in order to reduce its binding affinity towards SP without compromising too much on its antimicrobial potential (DHPS binding potential) and in the process identify structural elements responsible for this effect. Haruki, H., Pedersen, M.G., Gorska, K.I., Pojer, F., Johnsson, K. Tetrahydrobiopterin biosynthesis as an offtarget of sulfa drugs (2013) Science 340:
29 Modulations of sulfasalazine were inspired from (SR inactive) sulfamethazine, therefore it was decided to introduce various substituents on the heterocyclic ring (indicated by red color) next to the sulfonamide group in sulafasalazine as shown below:
30 Brief Methodology Crystal structure of human SR co-crystallized with sulfasalazine was downloaded from the PDB (PDB id 4J7X) BioSolveIT s LeadIT and SeeSAR software were used for docking and CADD respectively Self-docking of sulfasalazine into human SR was able to reproduce experimentally observed bound conformation with <2Å rmsd Scaffold hopping was used to generate new composite molecules All composite molecules were docked into hsr (4j7X) and bacterial DHPS enzyme from Streptococcus pneumoniae (2VEG) To validate docking protocol, self docking with 2VEG was also carried out All docked conformations were screened and ranked on basis of docking score
31 4J7X, sulfasalazine (purple) bound with hsr
32 Binding site interactions of sulfasalazine with hsr as observed in self docking using 4J7X
33 Entry Sulfasalazine (most active SR inhibitor) Structure Docking Scores SR Inhibition DHPS Inhibition difference Sulfamethazine (least active SR inhibitor)
34 Binding site interactions of sulfamethazine with hsr
35 Docked conformation of sulamethazine (non-inhibitor of SR) after HYDE analysis Binding Free Energy = -15 kj/mol
36 Docked conformation of sulamethazine (non-inhibitor of SR) overlapped with co-crystallized sulfasalazine shown in green (most active SR inhibitor)
37 Docked conformation of sulfasalazine (most active SR inhibitor) docked against hsr Docked conformation of sulfamethazine (noninhibitor) docked against hsr
38 Sulfasalazine was found to be the potent inhibitor with IC 50 value of 7 nm [Haruki 2013], whereas the least active sulfa drug was sulfamethazine (IC 50 = nm), and due to its very weak inhibition it was used as a negative control. In their study, the authors speculated that poor inhibition of sulfamethazine may be due to the presence of methyl substituents on the heterocyclic ring joined to the sulfonamide group.
39 Entry Structure Docking Scores SR Inhibition DHPS Inhibition difference * *
40 Entry` Structure Docking Scores SR Inhibition DHPS Inhibition difference * * *
41 Entry` Structure Docking Scores SR Inhibition DHPS Inhibition difference * * *
42 Entry` Structure Docking Scores SR Inhibition DHPS Inhibition difference * * *
43 Entry` Structure Docking Scores SR Inhibition DHPS Inhibition difference * The entries highlighted in yellow indicate molecules with greatest difference between docking score of SR and DHPS binding
44 Composites 11 and 12 were found to have least SR binding and most DHPS binding Entry` Structure Docking Scores SR Inhibition DHPS Inhibition difference * *
45 Docked conformation of molecule 11 with DHPS
46 Binding affinity analysis using HYDE of docked composite molecule 11 bound with DHPS Binding free energy = -29 kj/mol
47 Binding affinity analysis using HYDE of docked composite molecule 11 against hsr Binding free energy = -16 kj/mol
48 Binding affinity analysis using HYDE of docked composite molecule 11 against hsr Co-crystallized sulfasalazine is shown in green The new composite molecule 11, probably because of its bulky nature, does not go deep into the binding site pocket as sulfasalazine does
49 Binding affinity analysis using HYDE of docked composite molecule 12 bound with DHPS Binding free energy = -25 kj/mol
50 Binding affinity analysis using HYDE of docked composite molecule 12 bound with hsr Binding Free Energy = -14 kj/mol
51 Binding affinity analysis using HYDE of docked composite molecule 12 bound with hsr Sulfasalazine is shown in green
52 Summary The use of sulfa drugs to fight against bacterial infections had revolutionized medicinal chemistry, henceforth many researchers and pharmaceutical industries have successfully developed many new, effective antimicrobial drugs. Due to the rapid development of drug resistance, in particular the antibacterial drug resistance, it is essential that new drugs be introduced in the market. However, drug development, and bringing a new drug into the market is quite an expensive feat, and whereas new antibacterial drugs have been, and are being introduced with promising results, many researchers believe it is far more economical to re-design existing drugs, based on known pharmacophores. While sulfa drugs have saved many lives and are very effective antibacterial drugs, their use today is diminished, mainly due to the large number of patients suffering from sulfa allergies, or side effects from sulfa drugs. In 2013, researchers were able to demonstrate that CNS (central nervous system) related side effects of sulfa drugs are due to their binding to an off-target enzyme, sepiapterin reductase (SR). In this work, we have modulated the structure of sulfa drugs, using in-silico computational techniques, in order to reduce its binding affinity towards SR without compromising too much on its antimicrobial potential (dihydropteroate synthase (DHPS) binding potential), and in the process identify structural elements responsible for this effect. The in-silico modified/designed compounds were docked into SR as well as into bacterial enzyme DHPS (the main target of sulfa drugs). Some new molecules were identified that had lower affinity towards the offtarget SR, and greater binding affinity towards the antibacterial target, DHPS.
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