In Silco pharmacological action of selegiline an dother selective monooxidase B inhibitor

Selegiline, a medication used to treat Parkinson's disease and depression, belongs to a class of drugs called selective monoamine oxidase type B (MAO-B) inhibitors. Our brains use monoamine oxidase (MAO) enzymes to break down certain chemicals called neurotransmitters. These neurotransmitters, including dopamine, serotonin, and norepinephrine, play vital roles in mood, movement, and other bodily functions. In Parkinson's disease, dopamine levels are depleted, leading to symptoms like tremors and stiffness.

Selegiline acts by selectively inhibiting the MAO-B enzyme. This prevents the breakdown of dopamine, allowing more of it to remain active in the brain. This increased dopamine activity helps improve symptoms in Parkinson's patients. At higher doses, selegiline can also inhibit the MAO-A enzyme, affecting serotonin and norepinephrine levels. However, its primary use leverages its selective action on MAO-B for targeted dopamine modulation.

Other selective MAO-B inhibitors exist, but selegiline is known for its unique properties, including its irreversible binding to the MAO-B enzyme, leading to sustained effects

1. In Silco pharmacological action of selegiline and other selective Monoamine oxidase B Inhibitor A research proposal

2. To: Dr. Najeeb Ullah By: Samika Sharif Roll No: MS-BCE-22-10 Session: 2022-2024(Evening) A research proposal Submitted

3. Excellence: Quality and pertinence of the project’s research and innovation objectives. This project tackles Parkinson's disease, a major health concern, by developing improved MAO-B inhibitors, a proven treatment approach. It utilizes innovative computer methods to design new drugs with better effectiveness and fewer side effects. By addressing limitations of current medications, the research aims for a significant advancement in Parkinson's disease treatment.

4. Soundness of the proposed methodology : Sound Methodology: The review leverages established in silico methods like molecular docking and SAR analysis, proven for understanding drug-target interactions. (Bullet point: Proven in silico techniques) Multifaceted Approach: By combining docking, SAR analysis, and potentially other methods, the review offers a comprehensive analysis. (Bullet point: Comprehensive analysis through combined techniques) Beyond Inhibition: This multifaceted approach goes deeper than just looking at MAO-B inhibition, potentially revealing new mechanisms of action. (Bullet point: Potential to uncover new mechanisms) Development Focus: Ultimately, the review aims to translate these in silico insights into the development of more effective MAO-B inhibitors for Parkinson's treatment. (Bullet point: Informs development of next-generation MAO-B inhibitors)

5. 1. Molecular docking : docking simulations to assess how MAO-B inhibitors, including selegiline, bind to the MAO-B protein. It will focus on both the strength (binding affinity) and orientation (binding modes) of these inhibitors within the protein's active site. Finally, comparisons will be made to identify inhibitors with potentially superior binding or selectivity for MAO-B. 2 . Pharmacophore Modeling The review will dissect pharmacophore models to identify the key chemical features crucial for MAO-B inhibitor activity. It will explore how these features interact with the protein and their potential for guiding the design of new and effective MAO-B inhibitors. 3. Structure-Activity Relationship (SAR) Analysis The review will use SAR analysis to see how changes in MAO-B inhibitor structure (like selegiline) affect binding and side effects. This will help identify features for better potency, reduced MAO-A inhibition, and less TAAR1 impact, ultimately aiding design of new, optimized inhibitors. 4. Network Pharmacology Network pharmacology examines how MAO-B inhibitors (including selegiline) interact with a network of proteins and pathways. This reveals their broader effects beyond just MAO-B inhibition. The review will use this to identify new drug targets or combinations for more effective Parkinson's treatments Overall methodology

6. 1. Molecular docking : docking simulations to assess how MAO-B inhibitors, including selegiline, bind to the MAO-B protein. It will focus on both the strength (binding affinity) and orientation (binding modes) of these inhibitors within the protein's active site. Finally, comparisons will be made to identify inhibitors with potentially superior binding or selectivity for MAO-B. 2 . Pharmacophore Modeling The review will dissect pharmacophore models to identify the key chemical features crucial for MAO-B inhibitor activity. It will explore how these features interact with the protein and their potential for guiding the design of new and effective MAO-B inhibitors. 3. Structure-Activity Relationship (SAR) Analysis The review will use SAR analysis to see how changes in MAO-B inhibitor structure (like selegiline) affect binding and side effects. This will help identify features for better potency, reduced MAO-A inhibition, and less TAAR1 impact, ultimately aiding design of new, optimized inhibitors. 4. Network Pharmacology Network pharmacology examines how MAO-B inhibitors (including selegiline) interact with a network of proteins and pathways. This reveals their broader effects beyond just MAO-B inhibition. The review will use this to identify new drug targets or combinations for more effective Parkinson's treatments Overall methodology

7. Gender balance: This addresses the representation of genders within research studies.
Ensuring gender balance in research involves recruiting participants of diverse genders and considering gender-specific factors in data analysis and interpretation.
In the context of the abstract, it may indicate whether gender differences in response to MAO-B inhibitors are considered in the reviewed literature. Open science practices: Open science practices involve making research methods, data, and findings openly accessible and transparent.
This can include publishing research papers in open-access journals, sharing data and code openly, and engaging in collaborative and reproducible research practices.
In the context of the abstract, it could refer to whether the reviewed studies adhere to open science principles by sharing their methodologies, data, and findings openly.

8. Research data management and management of other research outputs: This involves the organization, storage, and sharing of research data and other outputs generated during the research process.
Effective research data management ensures that data are properly documented, stored securely, and made accessible for future use.
In the context of the abstract, it may address how the reviewed studies manage and share their research data, as well as any other outputs such as software code or model Quality of the two-way transfer of knowledge: This refers to the exchange of knowledge between researchers and other stakeholders, such as clinicians, patients, policymakers, and the public.
Quality transfer of knowledge involves effective communication, collaboration, and dissemination of research findings to ensure they are understood and utilized by relevant parties.
In the context of the abstract, it could assess how well the reviewed studies facilitate the transfer of knowledge between researchers and stakeholders, particularly regarding the development of MAO-B inhibitors for neurological disorders.

9. 1.Identification of Safer Inhibitors: By investigating inhibitors of Alr activity and focusing on finding safer alternatives to those currently available, the research could lead to the discovery of new compounds with antibacterial properties. This could significantly expand the repertoire of antibacterial agents available for combating antibiotic resistance, particularly in the context of E. faecium infections. 2 . Understanding pH Dependence:  The discovery that Alr performs optimally at pH 9 in E. faecium provides new insights into the environmental conditions that influence enzyme activity. This understanding of pH dependence could have broader implications for the development of antimicrobial strategies targeting bacterial cell wall synthesis. 3. Identification of Vital Residues: By identifying two important residues crucial for Alr's function, the research sheds light on the molecular mechanisms underlying enzyme activity. This knowledge could inform future drug design efforts by providing targets for rational drug design and optimization. 4 .Investigation of Allosteric Modulation: The exploration of possible allosteric impacts on Alr's function represents a novel avenue of research. By examining conserved contacts on its dimer interface and identifying potential drug-binding sites, the research could uncover new mechanisms for modulating enzyme activity and develop innovative strategies for antibacterial drug development. New knowledge gained by researcher

10. The previously acquired knowledge and skills that the researcher will transfer to the Host Organization: Here's an outline of some of the key expertise and experiences the researcher will transfer to the Host Organization: Ø Neuropharmacology: In-depth knowledge of the nervous system, particularly neurodegenerative diseases like Parkinson's disease and the role of dopamine, serotonin, and norepinephrine. Ø MAO Inhibitors: Expertise in the mechanisms of action of selegiline and other MAO-B inhibitors, including their impact on MAO-B activity and potential off-target effects on MAO-A and TAAR1. Ø In Silico Methods: Experience and proficiency in utilizing various computational techniques for drug discovery, including: o Molecular Docking: Simulating and analyzing the interaction between drug molecules and target proteins. o Pharmacophore Modeling: Identifying the key chemical features essential for a drug's biological activity. o Structure-Activity Relationship (SAR) Analysis: Understanding how structural modifications of a drug molecule affect its potency and selectivity. o Network Pharmacology: Investigating the complex interactions between drugs, their targets, and other biological pathways.

11. The quality and appropriateness of the researcher’s existing professional experience in relation to the proposed Host Organization, research group, supervisor and the research project. Here's an explanation of the quality and appropriateness of their experience: Ø Neuropharmacology: Understanding of neurodegenerative diseases like Parkinson's disease and the role of key neurotransmitters (dopamine, serotonin, norepinephrine). Ø MAO Inhibitors: Knowledge of selegiline and other MAO-B inhibitors, including their mechanisms of action and potential off-target effects. Ø In Silico Methods: Experience with computational drug discovery techniques like molecular docking, pharmacophore modeling, SAR analysis, and network pharmacology.

12. Alignment with Research Project: The proposed research project likely focuses on developing novel and more effective MAO-B inhibitors for Parkinson's disease or related neurological conditions. The researcher's expertise demonstrates a strong fit: Ø Expertise aligns with project goals: Their knowledge of neuropharmacology and MAO inhibitors directly addresses the project's therapeutic target. Ø In silico methods crucial for drug discovery: The proposed in silico methods (molecular docking, etc.) are central to designing and evaluating potential drug candidates. Ø Experience complements research group: The researcher's skills can complement the expertise of the host group, potentially leading to a well-rounded approach to the project. Alignment with Supervisor: The abstract doesn't provide details about the supervisor. However, assuming the supervisor has expertise in drug discovery or neuropharmacology, the researcher's background would likely benefit from the supervisor's guidance and vice versa, fostering a productive collaboration.