NOVEL HYBRIDS OF QUINOLINE LINKED PYRIMIDINE DERIVATIVES AS CYCLOOXYGENASE INHIBITORS: MOLECULAR DOCKING, ADMET STUDY, AND MD SIMULATION

DEEPTHI K; MANJUNATH S. KATAGI; JENNIFER FERNANDES; SHESHAGIRI DIXIT; DEEPSHIKHA SINGH

doi:10.22159/ijap.2024v16i6.52023

Authors

DEEPTHI K Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India https://orcid.org/0000-0002-9491-916X
MANJUNATH S. KATAGI Department of Pharmaceutical Chemistry, Bapuji Pharmacy College, Rajiv Gandhi University of Health Sciences, Davanagere-577004, Karnataka, India
JENNIFER FERNANDES Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore-575018, Karnataka, India https://orcid.org/0000-0002-9491-916X
SHESHAGIRI DIXIT Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy Mysore, JSS Academy of Higher Education and Research, Mysore-570015, Karnataka, India https://orcid.org/0000-0003-3966-7278
DEEPSHIKHA SINGH Department of Pharmaceutical Chemistry, JSS College of Pharmacy Mysore, JSS Academy of Higher Education and Research, Mysore-570015, Karnataka, India https://orcid.org/0000-0003-4030-5610

DOI:

https://doi.org/10.22159/ijap.2024v16i6.52023

Keywords:

Quinoline, Pyrimidine, Cyclooxygenase, Molecular docking, Molecular dynamics

Abstract

Objective: Finding novel anti-inflammatory compounds is a crucial sector of research despite the significant advances this field has made. Inefficiency and unfavorable side effects are indeed potential drawbacks of conventional therapy utilizing steroidal or nonsteroidal drugs. This study aims to screen the designed quinoline-linked pyrimidine derivatives as Cyclooxygenase (COX) inhibitors.

Methods: In the present study, we assessed the binding interactions of designed quinoline-linked pyrimidine derivatives with COX enzymes using a molecular docking approach. Using Molecular Dynamics (MD) simulations, the compound’s behavior was further investigated and its stability and conformational dynamics were demonstrated. Schrödinger's QikProp program was utilized to analyze the Absorption, Distribution, Metabolism, and Excretion (ADME) properties and toxicity properties were further investigated using Osiris Property Explorer. Additionally, the protein-ligand complexes' binding free energy has been ascertained using the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) approach, which offered crucial information regarding the strength of their interactions.

Results: The designed quinoline-linked pyrimidine derivatives fulfilled the Lipinski Rule of Five and had physicochemical characteristics within acceptable ranges, better ADME properties, and were non-toxic. Among the designed compounds, QPDU1 and QPDT6 showed correspondingly good docking scores for COX-1 and COX-2. QPDT6 was additionally analyzed by MD simulation studies to thoroughly examine the interaction between protein and ligand and their stability.

Conclusion: The proposed compounds exhibit strong binding affinities to COX enzymes, stable interactions in MD simulations, and favorable drug-like features. These results support the need for more research and development of these substances as possible anti-inflammatory drugs.

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