Abstract
CML originates due to reciprocal translocation in Philadelphia chromosome leading to the formation of fusion product BCR-ABL which constitutively activates tyrosine kinase signaling pathways eventually leading to abnormal proliferation of granulocytic cells. As a therapeutic strategy, BCR-ABL inhibitors have been clinically approved which terminates its phosphorylation activity and retards cancer progression. However, a number of patients develop resistance to inhibitors which demand for the discovery of new inhibitors. Given the drawbacks of present inhibitors, by high throughput virtual screening approaches, present study pursues to identify high affinity compounds targeting BCR-ABL1 anticipated to have safer pharmacological profiles. Five established BCR-ABL inhibitors formed the query compounds for identification of structurally similar compounds by Tanimoto coefficient based linear fingerprint search with a threshold of 95% against PubChemdatabase. Assisted by MolDock algorithm all compounds were docked against BCR-ABL protein in order to retrieve high affinity compounds. The parents and similars were further tested for their ADMET propertiesand bioactivity. Rebastinib formed higher affinity inhibitor than rest of the four established compound investigated in the study. Interestingly, Rebastinib similar compound with Pubchem ID: 67254402 was also shown to have highest affinity than other similars including the similars of respective five parents. In terms of ADMET properties Pubchem ID: 67254402 had appreciable ADMET profile and bioactivity. However, Rebastinib still stood as the best inhibitor in terms of binding affinity and ADMET properties than Pubchem ID: 67254402. Nevertheless, owing to the similar pharmacological properties with Rebastinib, Pubchem ID: 67254402 can be expected to form potential BCR-ABL inhibitor.
Keywords: Chronic Myeloid Leukemia, BCR-ABL, BCR-ABL1 inhibitors, Virtual screening methods, Kinase, ADMET, Leukemia.
Current Topics in Medicinal Chemistry
Title:A Virtual Screening Approach for the Identification of High Affinity Small Molecules Targeting BCR-ABL1 Inhibitors for the Treatment of Chronic Myeloid Leukemia
Volume: 17 Issue: 26
Author(s): Saphy Sharda, Palash Sarmandal, Shirisha Cherukommu, Kiran Dindhoria, Manisha Yadav, Srinivas Bandaru, Anudeep Sharma, Aditi Sakhi, Tanmay Vyas, Tajamul Hussain, Anuraj Nayarisseri*Sanjeev Kumar Singh*
Affiliation:
- Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu,India
- Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu,India
Keywords: Chronic Myeloid Leukemia, BCR-ABL, BCR-ABL1 inhibitors, Virtual screening methods, Kinase, ADMET, Leukemia.
Abstract: CML originates due to reciprocal translocation in Philadelphia chromosome leading to the formation of fusion product BCR-ABL which constitutively activates tyrosine kinase signaling pathways eventually leading to abnormal proliferation of granulocytic cells. As a therapeutic strategy, BCR-ABL inhibitors have been clinically approved which terminates its phosphorylation activity and retards cancer progression. However, a number of patients develop resistance to inhibitors which demand for the discovery of new inhibitors. Given the drawbacks of present inhibitors, by high throughput virtual screening approaches, present study pursues to identify high affinity compounds targeting BCR-ABL1 anticipated to have safer pharmacological profiles. Five established BCR-ABL inhibitors formed the query compounds for identification of structurally similar compounds by Tanimoto coefficient based linear fingerprint search with a threshold of 95% against PubChemdatabase. Assisted by MolDock algorithm all compounds were docked against BCR-ABL protein in order to retrieve high affinity compounds. The parents and similars were further tested for their ADMET propertiesand bioactivity. Rebastinib formed higher affinity inhibitor than rest of the four established compound investigated in the study. Interestingly, Rebastinib similar compound with Pubchem ID: 67254402 was also shown to have highest affinity than other similars including the similars of respective five parents. In terms of ADMET properties Pubchem ID: 67254402 had appreciable ADMET profile and bioactivity. However, Rebastinib still stood as the best inhibitor in terms of binding affinity and ADMET properties than Pubchem ID: 67254402. Nevertheless, owing to the similar pharmacological properties with Rebastinib, Pubchem ID: 67254402 can be expected to form potential BCR-ABL inhibitor.
Export Options
About this article
Cite this article as:
Sharda Saphy , Sarmandal Palash , Cherukommu Shirisha , Dindhoria Kiran, Yadav Manisha, Bandaru Srinivas , Sharma Anudeep , Sakhi Aditi , Vyas Tanmay , Hussain Tajamul , Nayarisseri Anuraj *, Singh Kumar Sanjeev *, A Virtual Screening Approach for the Identification of High Affinity Small Molecules Targeting BCR-ABL1 Inhibitors for the Treatment of Chronic Myeloid Leukemia, Current Topics in Medicinal Chemistry 2017; 17 (26) . https://dx.doi.org/10.2174/1568026617666170821124512
DOI https://dx.doi.org/10.2174/1568026617666170821124512 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Adaptogens—History and Future Perspectives
Adaptogens are pharmacologically active compounds or plant extracts that are associated with the ability to enhance the body’s stability against stress. The intake of adaptogens is associated not only with a better ability to adapt to stress and maintain or normalise metabolic functions but also with better mental and physical ...read more
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Current Pharmacological Treatment of Pulmonary Arterial Hypertension
Current Clinical Pharmacology Recent Progress in Pharmacological Research of Antioxidants in Pathological Conditions: Cardiovascular Health
Recent Patents on Anti-Infective Drug Discovery The Relationship Between Prolidase Activity and Atrial Electromechanical Changes in Patients with Paroxysmal Atrial Fibrillation
Combinatorial Chemistry & High Throughput Screening Patent Selections
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Nanocarriers Assisted siRNA Gene Therapy for the Management of Cardiovascular Disorders
Current Pharmaceutical Design Drug Repositioning: A Monetary Stratagem to Discover a New Application of Drugs
Current Drug Discovery Technologies The Emergence of Plasma Membrane Calcium Pump as a Novel Therapeutic Target for Heart Disease
Mini-Reviews in Medicinal Chemistry MicroRNAs: A Novel Non-Invasive Biomarker for Patients with Urological Malignancies
Current Pharmaceutical Biotechnology The Protein-Protein Interaction-Mediated Inactivation of PTEN
Current Molecular Medicine The Role of Hydrogen Sulfide and H2S-donors in Myocardial Protection Against Ischemia/Reperfusion Injury
Current Medicinal Chemistry The Application of NMR Spectroscopy for the Study of Heart Failure
Current Pharmaceutical Design Mitochondrial Dysfunction and Oxidative Stress in Insulin Resistance
Current Pharmaceutical Design Advanced Glycation End Products (AGEs), Glutathione and Breast Cancer: Factors, Mechanism and Therapeutic Interventions
Current Drug Metabolism CD93: Recent Advances and Implications in Disease
Current Drug Targets Obesity and Arterial Compliance Alterations
Current Vascular Pharmacology Recent Approaches for Angiogenesis in Search of Successful Tissue Engineering and Regeneration
Current Stem Cell Research & Therapy A Gastroretentive Drug Delivery System of Lisinopril Imbibed on Isabgol- Husk
Current Drug Delivery Diagnostic Value of MiR-125b as a Potential Biomarker for Stage I Lung Adenocarcinoma
Current Molecular Medicine Cell Penetrating Peptide Delivery of Splice Directing Oligonucleotides as a Treatment for Duchenne Muscular Dystrophy
Current Pharmaceutical Design Current and Potential Anticancer Drugs Targeting Members of the UHRF1 Complex Including Epigenetic Modifiers
Recent Patents on Anti-Cancer Drug Discovery