TARGETTING MUTATIONS WITH OLUTASIDENIL.pptx

GENETIC ENGINEERING IN THE FIELD OF SECTOR

1. "Targeting IDH1 Mutations with Olutasidenib: A Comprehensive Computational Study of Binding Interactions" Guide: Dr.R . Kamalambigeswari Associate professor Department of Biotechnology SIVASHREE .S U20BR038 Done By:

2. Index Abstract Introduction Review of Literature Imporatance of Topic Objective Methods Result Summary References 1 2 3 4 5 6 7 8 9

3. Introduction Cancer is a complex condition of cell differentiation in which abnormal cells multiply in a very uncontrolled, rapid or extreme manner. Normally, the body cells undergo cell division continuously which is essential for the growth, repair and reproduction. When the cell undergoes division, the cell which is damaged or aged dies by the process of apoptosis and the new cells takes their place. Sometimes, these damaged cells grow uncontrollably and form tumors which are a group of abnormal cells. These tumors grow invadly and spread to nearby tissues to form new tumors (metastasis).They can be beginin or malignant. There are numerous types of cancer on the basis of their body parts including brain, breast and liver etc. Beside from all types of cancers, leukemia and glioma is one of the most serious and worst health issues affecting the world today. Leukemia represents the cancer of bone marrow i.e., the place from where actual blood cells originate. In addition, cancer is divided into into two acute and chronic leukemia. In these two, acute leukemia spread at very quick and rapid manner by virtue of which needed to treat immediately. Nowadays, acute myeloid leukemia (AML) is very common and fast-growing blood cancer originated in myeloblast. In the person affected by AML, white blood cells proliferate in abnormal manner but these cells are useless to defend against current as well as upcoming infections.

4. Olutasideneib is also known as rhzelidia or FT-2102.The drug is also know as IDH1 inhibitor whivh entered the pharamocological department for AML patients approved by FDA in 2022.The drug suppresses the activity of idh1 mutation and plays the role of protecting the cells.The drug selectively binds with the mutant IDH1 other than wild type IDH isoforms present in myeoblasts.olutasideneib is available in the market in the brand name of rizeledia. In this study we are going to analyze the Olutasideneib against IDH1 enzyme through molecular dynamics and DFT analysis. The study provides the physical movements of atoms and molecules present in the receptor-ligand complex and the geometries then molecular electrostatic potential of the compound. In drug design, these analysis helps to know about the interactions between the receptor-drug, mechanism of action and properties of drug and the small molecules present at an atomic level.

5. S.NO. TITLE INFERENCE AUTHOR 1. Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 ( m IDH1) in cancer therapy This study stated that Gliomas mostly occur in the brain and, rarely, in the spinal cord. The treatment options for gliomas often requires a combinations of neurosurgical interventions, radiation therapy, and chemotherapy. In a recent report by the World Health Organization (WHO) on Glioma , Isocitrate dehydrogenase (IDH) mutations are recognized in over 80% of grade II/III cases. Also, in grade IV glioblastoma (GBM), IDH mutations were also frequently found in secondary GBM cases accounting for 73% of clinical cases. Thus mutations in IDH can be identified as effective therapeutic targets in treating gliomas . IDH mutations are mainly identified as mIDH1 and mIDH2 depending on the genes encoding the cytoplasmic and mitochondrial forms of IDH respectively. IDH mutations in cancer results in the suppression of normal cell differentiation and also cause the abnormal increase in epigenetic methylation of histones in DNA. Elliasu et al, 2021 2. Olutasidenib : A ray of hope in the treatment of acute myeloid leukaemia This study stated Olutasidenib , a potent IDH1m inhibitor is recommended to be administered orally in the dose of 150 mg, once a day. The maximum drug concentration ( Cmax ) of Olutasidenib can be exposed through food interaction (especially high fat containing meal). Hence, Olutasidenib is recommended to be taken in prescribed dose with empty stomach at least 1 hour before or 2 h after the meal taken. Olutasidenib without food interactions towards high fat meal reduces the probabilities of serious adverse effects associated with its high plasma drug concentration Bhupender Nehra , 2023 REVIEW OF LITERATURE

6. S.NO. TITLE INFERENCE AUTHOR 3. Molecular dynamics simulation for all This study stated Molecular dynamics (MD) simulations predict how every atom in a protein or other molecular system will move over time, based on a general model of the physics governing interatomic interactions ( Karplus and Mc Cammon , 2002). These simulations can capture a wide variety of important biomolecular processes, including conformational change, ligand binding, and protein folding, revealing the positions of all the atoms at femtosecond temporal resolution. Importantly, such simulations can also predict how biomolecules will respond—at an atomic level—to perturbations such as mutation, phosphorylation, protonation, or the addition or removal of a ligand. MD simulations are often used in combination with a wide variety of experimental structural biology techniques, including x-ray crystallography, cryo -electron microscopy ( cryo -EM), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and Förster resonance energy transfer (FRET).These simulations are powerful for several reasons. First, they capture the position and motion of every atom at every point in time, which is very difficult with any experimental technique. Second, the simulation conditions are precisely known and can be carefully controlled: the initial conformation of a protein, which ligands are bound to it, whether it has any mutations or post-translational modifications, which other molecules are present in its environment, its protonation state, the temperature, the voltage across a membrane, and so on. Scott A. Hollingsworth, 2019

7. AIM This project aims to investigate the inhibitory potential of Olutasidenib (FT-2102) against mutated IDH1, implicated in glioma and acute leukemia. Utilizing molecular dynamics and DFT analysis, we seek to understand the structural properties of Olutasidenib's interaction with IDH1, evaluate its dynamic properties, and contribute insights for the development of targeted therapies against IDH1-associated cancers.

8. METHODS MOLECULAR DYNAMICS SOLVENT ACCESSIBLE SURFACE AREA

9. METHODS MOLECULAR DYNAMICS Molecular dynamics (MD) simulations predict how every atom in a protein or other molecular system will move over time, based on a general model of the physics governing interatomic interactions. These simulations can capture a wide variety of important bio molecular processes, including conformational change, ligand binding, and protein folding, revealing the positions of all the atoms at femtosecond temporal resolution. Importantly, such simulations can also predict how biomolecules will respond at an atomic level to perturbations such as mutation, phosphorylation, protonation, or the addition or removal of a ligand. While crystallographic studies like these convincingly demonstrate the important role protein flexibility plays in ligand binding, the expense and extensive labor required to generate them have led many to seek computational techniques that can predict protein motions. Unfortunately, the calculations required to describe the absurd quantum-mechanical motions and chemical reactions of large molecular systems are often too complex and computationally intensive for even the best supercomputers. The atomic forces that govern molecular movement can be divided into those caused by interactions between atoms that are chemically bonded to one another and those caused by interactions between atoms that are not bonded. Chemical bonds and atomic angles are modeled using simple springs, and dihedral angles.

10. DFT ANALYSIS In drug design and medicinal chemistry, DFT is considering as most efficient and significant method. In DFT, firstly we have to determine an important property that is electronic density ρ. By using electronic density ρ, we can determine easily ground energy state and all other properties of molecules. In drug design , the method plays a active role in recent studies. Density Functional Theory (DFT) has come into lightwhich offers excellent level of accuracy with lesser computational time compared to other methods.

11. RESULTS Molecular dynamics (MD) simulations predict how every atom in a protein or other molecular system will move over time, based on a general model of the physics governing interatomic interactions. These simulations can capture a wide variety of important bio molecular processes, including conformational change, ligand binding, and protein folding, revealing the positions of all the atoms at femtosecond temporal resolution. Importantly, such simulations can also predict how biomolecules will respond at an atomic level to perturbations such as mutation, phosphorylation, protonation, or the addition or removal of a ligand. Molecular dynamics was done in GROMACCS.To know the complex interactions in atomic level we need to modify the complex for better vizulaization.The input was created using CHARMM-GUI for both free and target protein with the default system.

12. B – complex protein C – free protein

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