Abstract
Protein Kinase C βII (PKCβII) overexpression has been linked to various diabetic microvascular complications viz. retinopathy, neuropathy, and cardiomyopathy. Novel and potent small molecules with preferential selective inhibitory property of PKCβII will be helpful in treatment as well as understanding insight of PKCβII involvement in these complications. Robust 3D hypotheses were developed using both the crystal structure and available PKCβII ligands, and were validated by feature mapping and screening in-house database of reported PKCβII compounds. The best hypothesis from both methods consists of six features viz. one hydrogen bond donor (D), two hydrogen bond acceptors (A1, A2), two hydrophobic-aromatics (H1, H2) and one ring aromatic (R). A synergistic approach of virtual screening using both ligand and receptor based pharmacophore model was used for the flexible search of ligands from chemical databases. The hits obtained were screened by molecular docking and their binding affinity was predicted using MMPBSA calculations. The first receptor based query of PKCβII and new scaffold of its inhibitors with good estimated activities, favorable binding interactions, and high docking score were identified.
Keywords: Molecular docking, molecular dynamics, pharmacophore modeling, PKCβII inhibitors, scaffold, virtual screening.
Combinatorial Chemistry & High Throughput Screening
Title:Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study
Volume: 17 Issue: 1
Author(s): Baljinder K. Grewal and Masilamani E. Sobhia
Affiliation:
Keywords: Molecular docking, molecular dynamics, pharmacophore modeling, PKCβII inhibitors, scaffold, virtual screening.
Abstract: Protein Kinase C βII (PKCβII) overexpression has been linked to various diabetic microvascular complications viz. retinopathy, neuropathy, and cardiomyopathy. Novel and potent small molecules with preferential selective inhibitory property of PKCβII will be helpful in treatment as well as understanding insight of PKCβII involvement in these complications. Robust 3D hypotheses were developed using both the crystal structure and available PKCβII ligands, and were validated by feature mapping and screening in-house database of reported PKCβII compounds. The best hypothesis from both methods consists of six features viz. one hydrogen bond donor (D), two hydrogen bond acceptors (A1, A2), two hydrophobic-aromatics (H1, H2) and one ring aromatic (R). A synergistic approach of virtual screening using both ligand and receptor based pharmacophore model was used for the flexible search of ligands from chemical databases. The hits obtained were screened by molecular docking and their binding affinity was predicted using MMPBSA calculations. The first receptor based query of PKCβII and new scaffold of its inhibitors with good estimated activities, favorable binding interactions, and high docking score were identified.
Export Options
About this article
Cite this article as:
Grewal K. Baljinder and Sobhia E. Masilamani, Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study, Combinatorial Chemistry & High Throughput Screening 2014; 17 (1) . https://dx.doi.org/10.2174/1386207311301010008
DOI https://dx.doi.org/10.2174/1386207311301010008 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
- 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
Related Articles
-
Meet Our Editorial Board Member:
Current Diabetes Reviews Editorial (Thematic Issue: Mechanistic Biomarkers: The Field for the Development of Non-Pharmaceutical and Pharmaceutical Approaches to Diagnostics, Prevention and Treatment of Chronic Diseases)
Current Pharmaceutical Design Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches
Current Pediatric Reviews MDMA Toxicity and Pathological Consequences: A Review About Experimental Data and Autopsy Findings
Current Pharmaceutical Biotechnology Cardiotoxicity of Molecularly Targeted Agents
Current Cardiology Reviews Cardiovascular Complications in Diabetes: Lessons from Animal Models
Current Medicinal Chemistry Sirtuin Modulators: Mechanisms and Potential Clinical Implications
Current Medicinal Chemistry Cardiovascular Complications of Obesity
Current Respiratory Medicine Reviews New Perspectives of Infections in Cardiovascular Disease
Current Cardiology Reviews Therapeutic Angiogenesis in Ischemic Tissues by Growth Factors and Bone Marrow Mononuclear Cells Administration: Biological Foundation and Clinical Prospects
Current Stem Cell Research & Therapy Parvovirus B19 (B19V) Infection and Pregnancy
Current Pediatric Reviews Mechanical Circulatory Support in Children
Current Cardiology Reviews Proteomic and Bioinformatic Analysis of Trypanosoma cruzi Chemotherapy and Potential Drug Targets: New Pieces for an Old Puzzle
Current Drug Targets Sympathetic Activation in Congestive Heart Failure: Evidence, Consequences and Therapeutic Implications
Current Vascular Pharmacology Common Genetic Conditions of Ischemic Stroke to Keep in Mind
Current Molecular Medicine Clear Shot at Primary Aim: Susceptibility of Trypanosoma cruzi Organelles, Structures and Molecular Targets to Drug Treatment
Current Topics in Medicinal Chemistry Prevalence of Major Cardiac Events of Anthracycline-Induced Cardiotoxicity in Southwestern Iran: Different Response Patterns to Cumulative Dose
Current Drug Therapy Role of Iron Deficiency and Overload in the Pathogenesis of Diabetes and Diabetic Complications
Current Medicinal Chemistry Targeting ADAM12 in Human Disease: Head, Body or Tail?
Current Pharmaceutical Design Malignancy and Radiation-Induced Cardiotoxicity
Cardiovascular & Hematological Disorders-Drug Targets