Molecular Modeling Approach to Cardiovascular Disease Targetting

(1)

MOLECULAR MODELING APPROACH

TO CARDIOVASCULAR DISEASE

TARGETTING

CHANDRA SEKHAR AKULA * (1), PROF. ALLAM APPA RAO (2), SAMEERA.P (3), SURESH

KUMAR.SANGEETA (4), SATEESH PATCHIKOLLA

1. Associate Professor, Dept. of Computer Science Lendi Institute of Engg. And

Technology, Vizianagaram, A.P, India. 2. Vice Chancellor, Jawaharlal Nehru Technological University: Kakinada, Kakinada 533 003, A.P, India. 3. P.sameera, Msc Bioinformatics, Gitam University: Visakhapatnam

A.P, India. 4. Suresh Kumar Sangeeta, Msc Bioinformatics, Gitam University: Vishakhapatnam. A.P, India. 5. Associate Professor, Dept. of Computer Science, M.V.G.R College of Engg., ABSTRACT

Cardiovascular disease, including stroke, is the leading cause of illness and death in the India. A number of studies have shown that inflammation of blood vessels is one of the major factors that increase the incidence of heart diseases, including arteriosclerosis (clogging of the arteries), stroke and myocardial infraction or heart attack. Studies have associated obesity and other components of metabolic syndrome, cardiovascular risk factors, with low-grade inflammation. Furthermore, some findings suggest that drugs commonly prescribed to the lower cholesterol also reduce this inflammation, suggesting an additional beneficial effect of the stains. The recent development of angiotensin 11 (Ang11) receptor antagonists has enabled to improve significantly the tolerability profile of this group of drugs while maintaining a high clinical efficacy. ACE2 is expressed predominantly in the endothelium and in renal tubular epithelium, and it thus may be an import new cardiovascular target. In the present study we modeled the structure of ACE and designed an inhibitor through using ARGUS lab and the validation of the Drug molecule is done basing on QSAR properties and Cache for this protein through CADD.

KEY WORDS:

Cardiovascular Disease (CVD) , C-reactive protein (CRP), Angiotensin converting enzyme (ACE) INTRODUCTION:

WHAT IS DISEASE?

Cardiovascular Disease (CVD) includes dysfunctional conditions of the heart, arteries, and veins that supply oxygen to vital life-sustaining areas of the body like the brain, the heart itself, and other vital organs. If oxygen doesn't arrive the tissue or organ will die.Excess buildups of fat or plaque are respectively termed arteriosclerosis and atherosclerosis. Equally significant would be inadequate oxygen flow to the brain, which causes a stroke.

High Blood Pressure (hypertension) often results from this excess fat or plaque buildup because of the extra effort it takes to circulate blood. Even though the heart works harder, blockages still shortchange the needed blood supply to all areas of the body. The body's amazing survival systems will mask the subtle damage that is occurring from this extra wear and tear, but not forever. High blood pressure is called "The Silent Killer" because the first warning sign is an angina attack or a deadly heart attack or a stroke.Infection of the heart, carditis and endocarditis, is an

(2)

Damage to the heart tissues from CVD or from heart surgery will disrupt the natural electrical impulses of the heart and result in cardiac arrhythmia (an abnormally high or abnormally low heart rate). Individuals often don't realize the aftermath and side effects that invasive surgical procedures leave. Sudden fluctuations in heart rate can cause noticeable palpitations, with an associated faintness, or dizziness, and if severely abnormal could interfere with blood flow and even initiate a heart attack.

GENES RESPONSIBLE FOR DISEASE

The term "cardiovascular disease" is used to describe over 60 conditions that affect the heart so the genes will also vary for each blood vessel. The genes responsible for genes are as follows-

Cre: CHLREDRAFT_206018: ribosome biogenesis pescadillo-like protein

Sce:YDR423C: CAD1; AP-1-like basic leucine zipper (bZIP) transcriptional activator involved in stress responses, iron metabolism, and pleiotropic drug resistance; controls a set of genes involved in stabilizing proteins; binds consensus sequence TTACTAA; K09043 fungal AP-1-like factor

Ncr: NCU00925: similar to ribosome biogenesis protein Pescadillo. Afm: AFUA_4G08190: ribosome biogenesis protein Pescadillo. Afv: AFLA_111610: ribosome biogenesis protein Pescadillo, putative. Act: ACLA_047550: ribosome biogenesis protein Pescadillo, putative. Nfi: NFIA_107990: ribosome biogenesis protein Pescadillo, putative. TARGETING PROTEIN FOR CARDIOVASCULAR DISEASE

Elevated levels of C-reactive protein (CRP) are associated with an increased risk for cardiovascular events, such as heart attack and stroke. But it has been unclear whether CRP actually causes these cardiovascular problems, or rather is merely a "marker" for increased risk. This question has potential importance, since drug companies are actively developing medications aimed specifically at reducing CRP levels. (Reducing CRP levels would not be expected to improve outcomes if CRP is merely a marker and not a causitive agent).

(3)

PATHWAY OF THE PROTEIN CAUSING DISEASE

Fig 1: Diagram representing the pathway of ACE , from KEGG Database

RESULTS

Template selection: The template for this protein was selected from the server swiss model server. The identified Templates are 1o8aA and 1uzeA.

(4)

The Active sites for the modeled Protein were identified using Qsite finder.

I. INDIVIDUAL DOCKING WITH DRUGS

Docking the drugs with the modeled ACE protein using Argus lab the results are elucidated below. 1. CAPTOPRIL: Best Ligand Pose: energy = -6.07037Kcal/mol

Docking Run : Elapsed time = 19sec 2. GEMFIBROZIL: Best Ligand Pose: energy = -5.75246Kcal/mol Docking Run : Elapsed time = 32sec 3. ISOVALERIC ACID: Best Ligand Pose: energy = -7.14431Kcal/mol Docking Run : Elapsed time = 22sec 4. QUINOPRIL: Best Ligand Pose: energy = -6.13296Kcal/mol Docking Run : Elapsed time = 40sec 5. FLUVASTATIN: Best Ligand Pose: energy = -6.82398Kcal/mol Docking Run : Elapsed time = 15se

(5)

II. QSAR Properties for Cinnamyl isovalerate (Using HYPERCHEM): Partial charges: 0.00e

Surface Area: 548.70Å² Surface Area grid: 438.32Å² Volume: 677.10Å³ Hydration Energy: -2.32 Kcal/mol Log P: 0.97

Refractivity: 48.44Å³ Polarizibility: 16.81Å³ Mass: 200.15amu

III. Available drugs and their similar drug candidates.

Available Drugs Similar drugs ID’s captopril Captopril nem sulfoxide

captopril disulfide cinnamyl isovalerate

CID: 163066 CID: 194814 CID: 44148746

FLUVASTATIN

cyclohexyl isovalerate gemfibrozil M3

CID: 23685001 CID: 24838623

GEMFIBROZIL

geranyl isovalerate CID: 88118

ISOVALERIC ACID

Lescol

Phenethylamine Primisen Quinaprilat

(6)

Cinnamyl isovalerate

UV Visible Transition Graph: IR Transition Graph:

Diplaying the graph of final drug molecule Diplaying the graph of final drug molecule after UV visible transition using CaChe after IR transition using Cache

IV.Comparative docking results of similar drugs with respect to already available five drugs using Vezza. Summary of results in order of docking score (kcal/mol)

******************************************************** 1. Cinnamyl isovalerate -11.0976

(7)

4. Cyclohexyl isovalerate -6.28155 Elapsed time for calculation = 43 seconds 887 Thr:

Summary of results in order of docking score (kcal/mol) 992 His:

Summary of results in order of docking score (kcal/mol)

******************************************************** 1. Phenethylamine -6.55336

2. Cinnamyl isovalerate -6.53962 3. Geranyl isovalerate -6.53962 4. Cyclohexyl isovalerate -3.58104 Elapsed time for calculation = 31 seconds 1020 Asp:

******************************************************** 1. Cinnamyl isovalerate -9.00227

2. Geranyl isovalerate -9.00227 3. Phenethylamine -7.89499 4. cyclohexyl isovalerate -4.28985 Elapsed time for calculation = 35 seconds 1059 Lys:

******************************************************** 1. Phenethylamine -9.17807

2. Cinnamyl isovalerate -8.90184 3. Geranyl isovalerate -8.90184 4. Cyclohexyl isovalerate -6.0759 Elapsed time for calculation = 27 seconds 751 Tyr:

******************************************************** 1. Cinnamyl isovalerate -9.90097

2. Geranyl isovalerate -9.90097 3. Phenethylamine -8.15269 4. Cyclohexyl isovalerate -6.37108 Elapsed time for calculation = 27 seconds

Discussion:

Angiotensin-Converting Enzyme (ACE) is a protein which is causing cardio vascular diseases. Genomic, proteomic and phylogentic analysis were done by using BIOEDIT where in genomics graphical representation of nucleotide composition and restriction mapping were analyzed, in proteomics graphical representation of amino acid composition is obtained and in phylogentic analysis different related proteins were analyzed which is represented in trees.

The current problem of the research is ACE protein is having co-crystals in its structure which are disturbing the docking ability of the ligand with that of the receptor. In order to remove the co-crystal from the receptor the protein structure is refined to remove the co-crystals and other impurities. In the first step of work flow the template sequence of the ACE protein is obtained by submitting the structure to the SWISSPROT. Then the structure is re-built for the template sequence by homology modelling using SWISS PDB Viewer.

The homology modeled protein is then docked with the existing drugs and the most effective G was noted. Then a database of ligands was created by using the existing drugs as templates and few ligands were designed for which virtual screening was done using Vega ZZ of which 5 molecules were selected.

(8)

affinity than the existing drugs of which cinnamyl iso-valerate is having more affinity when to compared to other drugs which can be further referred to QSAR for further studies.

Conclusion:

Specific protein causing the disease is identified as ACE INHIBITOR Homology modeling of the protein is done using SPDBV (Swiss PDB Viewer). Active site analysis is done through Q site finder method and the active site amino acids are noted. Standard available market drugs targeting the protein were identified as follows:

1. CAPTOPRIL 2. FLUVASTATIN 3. GEMFIBROZIL 4. ISOVALERIC ACID 5. QUINAPRIL

Similar molecules (11 drugs listed in the above table) for these standard molecules were modeled using Argus Lab. A database is created with all these molecules in Vega ZZ

Virtual Screening of these drugs is done through protein Vega ZZ database docking method. The results obtained show that cinnamyl isovalerate is interacting at the lowest energy level with all the amino acids in the potential active site, the results are shown in the above catalogue IV and through Cache analysis the lead Cinnamyl isovalerate is potential to UV and IR transitions. The QSAR Properties are also give the immense potential that the Selected lead is the Best Among the 11 molecules. So, we consider that ligand as the potential lead molecule to target the protein ACEII modeled protein in treating the disease.

References:

[1] www.arguslab.com/

[2] www.pdb.org

[3] www.ncbi.nlm.nih.gov

[4] www.expacy.org