Docking Studies of Serine Protease Inhibitor with Various SPI Activators to Treat COPD

Author Name: Chlumalla Srikanth, Rahul BharadwaJ
Author Email: shreekanthchelumalla@gmail.com

Abstract

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin, which is a type of serine protease inhibitor (serpin). Alpha-1 antitrypsin protects the lungs from neutrophil elastase, which can damage lung tissue if not properly controlled. The current work involves the complete annotation of SERPINA1 followed by analysing its role in COPD disease. The work can be extended in designing a potential ligand (drug) that can exhibit a good docking energy and can be used in the therapy of the same. By using different Bioinformatics Tools Structural & functional analysis of alpha-1 antitrypsin is done. Serpins (serine proteinase inhibitors) belong to MEROPS inhibitor family I4, clan ID. Several softwares and Databases have been used in the work. NCBI, Gene Cards, PDB, Pubchem were the databases used for collecting the protein Sequence, Functional Information, Structure and chemical compounds respectively. Certain tools like Dundee ProDrg Server, Protparam, CASTP etc are used for data analysis. The docking was performed using Hex software. Based on the energy values exhibited, the best ligand selected was Gabexate mesylate with its docking energy of – 264.27.

Keywords

SERPIN1A, Antitrypsin, Elastase, COPD, MEROPS inhibitor family, Protparam, CASTP

Introduction

COPD, or chronic obstructive pulmonary (PULL-mun-ary) disease, is a progressive disease that makes it hard to breathe. “Progressive” means the disease gets worse over time. COPD can cause coughing that produces large amounts of mucus (a slimy substance), wheezing, shortness of breath, chest tightness, and other symptoms. Cigarette smoking is the leading cause of COPD. Most people who have COPD smoke or used to smoke. Long-term exposure to other lung irritants—such as air pollution, chemical fumes, or dust—also may contribute to COPD. The airways and air sacs are elastic (stretchy). When you breathe in, each air sac fills up with air like a small balloon. When you breathe out, the air sacs deflate and the air goes out. In COPD, less air flows in and out of the airways because of one or more of the following: The airways and air sacs lose their elastic quality. The walls between many of the air sacs are destroyed. The walls of the airways become thick and inflamed. The airways make more mucus than usual, which can clog them.

In the United States, the term “COPD” includes two main conditions—emphysema (em-fih-SE-ma) and chronic bronchitis (bron-KI-tis). (Note: The Health Topics article about bronchitis discusses both acute and chronic bronchitis.)

In emphysema, the walls between many of the air sacs are damaged. As a result, the air sacs lose their shape and become floppy. This damage also can destroy the walls of the air sacs, leading to fewer and larger air sacs instead of many tiny ones. If this happens, the amount of gas exchange in the lungs is reduced.

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin, which is a type of serine protease inhibitor (serpin). Serpins help control several types of chemical reactions by blocking (inhibiting) the activity of certain enzymes. Alpha-1 antitrypsin prevents the digestive enzyme trypsin from breaking down proteins until trypsin reaches the intestines. Alpha-1 antitrypsin also inhibits other enzymes, including a powerful enzyme called neutrophil elastase that is released from white blood cells to fight infection. Alpha-1 antitrypsin protects the lungs from neutrophil elastase, which can damage lung tissue if not properly controlled. Alpha-1 antitrypsin is produced in the liver and then transported to the lungs via the blood.

More than 120 mutations in the SERPINA1 gene have been identified. Some of these mutations do not affect the production of alpha-1 antitrypsin, while others cause a shortage (deficiency) of the protein. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys the small air sacs in the lungs (alveoli) and causes lung disease. Excessive damage to the alveoli leads to emphysema, an irreversible lung disease that causes extreme shortness of breath.

Conclusion

In the above analysis the protein sequence of SERPINA1 was collected from NCBI and the functional study was undertaken in genecards. The protein sequence was used for the Sequence based analysis which includes Protparam for physic chemical characterization, SMART for Domain identification, String for network analysis etc. The protein structural analysis was performed using SOPMA and Phyre followed by its 3D visualization using Rasmol. The total binding sites present in the protein were identified using CASTP tool. The study was directed for Drug development using the regular CADD approach. Activators of serine protease inhibitor (serpin) are collected from the PubChem database, out of 108 Activators obtained only 68 activators are selected for analysis which followed lipinsky rule as they possess the drug likeliness. These chemicals were further screened for Ambiguity at the secondary screening level. For this Dundee Prodrg server has been used. The structures were downloaded from the same data base. A docking study was performed between the selected list of ligands and the one receptor SERPINA1 using HEX 8.0 Software. The final ligands with lowest binding energy was found to be Gabexate methylate which was selected as the best drug to target the above receptor. It can be used as a therapeutic drug to treat COPD.

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