A series of novel caffeic acid derivatives that were designed utilizing autodock vina software are being developed as a potent anti-sickling agent in an effort to produce anti-polymerizing activity that will lessen complications in sickle cell disease. When different chemical groups are substituted on the hydroxyl benzaldehyde ring at the meta-position to create caffeic acid analogues, docking studies reveal strong binding affinity to the protein's active region. The results of this study may lead to the development of more effective anti-sickling therapies. Caffeic acid, in its many forms, is one of the most promising secondary metabolites for the treatment of a wide range of illnesses and diseases. The toxicity & biological activity of 8 chemicals are analyzed in this study using ADMET and Auto dock vina software for calculating binding score. Out of 8 compounds from the Caffeic acid derivatives substitution at meta position can be regarded as the safest showing best binding affinity can be further synthesized to get new drug.
Research Article
In-Silico Drug Designing of Anti-Polymerizing Activity of Caffeic acid derivatives for the Treatment Of Sickle Cell Disease
https://doi.org/10.21203/rs.3.rs-2992344/v1
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Toxicity
ADMET SAR
Caffeic acid derivatives
Docking Studies
anti-polymerising activity
The most prevalent monogenic multisystem condition in the world, i.e. sickle cell anemia which is characterized by acute sickness and progressive organ deterioration. It is one of the most significant hemoglobinopathies in the world in terms of frequency and socio-economic impact, and the World Health Organisation recently recognized it as a concern of global public health. It is a multisystem, monogenic illness with a high morbidity and fatality rate. Since the 1980s, innovative methods for treating sickle cell disease have been implemented, such as the administration of newborn screening programmes, the introduction of penicillin prophylaxis for sickle cell children, and the use of transcranial Doppler screening for the detection of cerebral vasculopathy and the prevention of stroke. Better sickle cell therapies have long been recognized as being necessary by haematologists. The rigid RBC's cause a variety of problems There are now four authorized medicines for the treatment of SCD. One of them medicines is hydroxyurea (HU), which causes the production of foetal hemoglobin (Hb F) in order to prevent the polymerization of Hb S. Because about 30% of patients had less response, in part due to poor compliance, its use has been restricted. As it reduces oxidative stress, Endari or L-glutamine was licenced in 2017 for the treatment of SCD, but it was ineffective. Later, the FDA authorised the two additional medications Voxelotor (Oxybryta or GBT-440) and Crizanlizumab (Adakveo). As a monoclonal antibody that targets "P- selectin," Crizanlizumab reduces the frequency of painful Vaso-occlusive events. The Voxelotor, on the other hand, is an aromatic aldehyde that is connected to haemoglobin.
A powerful and capable tool for in silico screening is molecular docking. It is becoming increasingly more significant in the process of rational medication design. Finding a suitable ligand that fits the protein's binding site energetically and geometrically is a computational process called docking. In other terms, it is a study of the interaction between two or more molecules, such as a protein and a ligand. The challenge resembles a 3D puzzle to be solved. In-depth study has been done on the use of computational approaches in this field during the past ten years to better understand how intermolecular complexes occur. It is well known that molecular binding occurs when a ligand binds to the pocket of a receptor. In the current work, the pharmacophore hybrid technique is a very useful and frequently employed approach for exploring new and more potent molecules in contemporary chemistry. A molecule that has a general increase in potency or exhibits synergistic effects is produced by the union of two or more bioactive molecules in one unit. The administration of a single medication will result in more predictable pharmacokinetic and pharmacodynamic features as well as increased patient compliance, making single molecules that act on numerous targets a better treatment candidate than drug combinations. These considerations led us to suggest fusing three moieties—heterocyclic rings, an amino acid bridge, and aromatic hydroxyl benzaldehydes—into one. Prior to production, molecular docking was used to screen the candidate compounds in-silico. The proposed compounds were screened in-silico prior to synthesis employing molecular docking study then after most prominent compounds which were found active in docking giving good binding activity score, further toxicity predicted by ADMETSAR Software. Caffeic acid (3,4-dihydroxycinnamic acid) (CA) interacts with and inhibits the oxidative reactions of myoglobin (Mb) and hemoglobin (Hb), and this interaction underlies its antioxidative action in meat. It has strong antioxidant effect on Hb S that surpassed the effects of other small drug molecules investigated so far. Moreover, CA demonstrated an antisickling properties by increasing Hb delay time for polymerization. The most noticeable effect was the ability of Caffeic acid to considerably reduce HbFe4 + content formed during the reaction of peroxide and Hb 9,8.
PDB (www.pdb.org) was used to retrieve the structure of the target protein of sickled Hb (2HbS) with the protein databank identification number. The drug bank website (www.drugbank.ca) provided the structure of the drug caffeic acid. The drug derivatives are created using the Chem-Draw 16.0 software, and the minimized structure was chosen, docked, and visualized in Discovery Studio.
1) Protein Preparation :
In order to prepare the protein PDB ID-2HbS for minimization, water molecules, ligands, and hetero atoms are removed. Next, grid creation is performed. With the aid of online tools like PDB SUM and VISUALISER (DISCOVERY STUDIO), the active site of a protein can be determined.
2) Ligand Preparation :
The ligand was prepared by extracting structure from bio bank or drawing from Chem Draw and substituting the ligand caffeic acid with R1 = methyl nicotinate and by altering positions, 8 derivatives are formed.
3) Docking using Auto-dock vina software
In the current investigation, Auto- dock vina software was utilized to forecast how ligands would interact with proteins. The binding affinities of many ligands are predicted using molecular docking techniques. In this investigation, we looked into the possibility of a connection between the experimental bioactivities of the investigated inhibitors and the docking scores. All docking experiments were run with the default parameters in order to obtain realistic results. One ligand docked in about one to two minutes. FlexX was ran on a Windows 7-equipped computer, whereas AutoDock/Vina docking was carried out on a Linux workstation (openSUSE11.4) with an Intel Pentium D CPU running at 3.0 GHz. FlexX ran on Windows 7 with an Intel Atom 1.67 GHz processor and 1 GB of RAM, in contrast to FlexX, which ran on Windows 7. The Graphical User Interface programme AutoDock Tools (ADT) was used to perform intermediary tasks, such as creating grid boxes and pdbqt files for protein and ligand preparation. The protein was given by ADT polar hydrogens, unified atom Kollman charges, solvation parameters, and fragmental volumes. The prepared file was stored in PDBQT format by AutoDock. A grid box was utilised to create the grid map using AutoGrid. To reduce the amount of time needed for computation, a score grid is created from the ligand structure. Protein and ligand information was combined with grid box attributes from the setup file to use AutoDock/Vina for docking. AutoDock/Vina uses iterated local resources10.
|
s/no. |
Ligands ( SUBSTITUTION R1 AT DIFFERENT POSITION IN A RING) |
Binding energies (k/cal )mol |
|---|---|---|
|
1. |
CA 1 |
− 8.4 |
|
2. |
CA 2 |
-8.6 ( BEST ) META POSITION |
|
3. |
CA 3 |
-8.1 |
|
4. |
CA 4 |
-8.1 |
|
5. |
CA 5 |
-7.0 |
|
6. |
CA 6 |
-7.3 |
|
7. |
CA 7 |
7.2 |
|
8. |
CA 8 |
-7.8 |
|
9. |
CAFFEIC ACID |
-6.2 |
|
10. |
HYDROXYUREA ( Std.) |
-3.9 |
|
11. |
VOXELOTOR (Std.) |
-7.0 |
|
12. |
L- GLUTAMINE (Std.) |
-4.9 |
4) Toxicity analysis.
The toxicity of the compounds was estimated by ADMET SAR software .ADMET SAR of best docking score showing caffeic acid derivative .This software compares an intended chemical substance with detected and known toxic compounds1,2.
5) Bioactivity analysis.
Molinspiration website was also applied for analyzing bioactivity of caffeic acid derivative possessing best docking result.
|
GPCR ligand |
Ion channel modulator |
Kinase inhibitor |
Nuclear receptor ligand |
Protease inhibitor |
Enzyme inhibitor |
2D Structure |
|---|---|---|---|---|---|---|
|
-0.06 |
-0.12 |
-0.15 |
0.28 |
-0.10 |
0.14 |
|
Thus the in- silco method adopted in the present study helped in identifying the ligands using the commercial software and online tools for Anti- sickling activity. This method reduces the cost and time in designing a drug as well as in analyzing the drug likeliness and toxicity before it enters to the clinical trials.
Conflict of Interest :
The author declares no conflict of interest.
Acknowledgement:
Authors are deeply grateful to the Department of pharmacy, Guru Ghasidas Vishwavidyalaya Bilaspur C.G for research facilities.
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No competing interests reported.