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Computational discovery of AKT serine/threonine kinase 1 inhibitors through shape screening for rheumatoid arthritis intervention.
Rangaswamy, Raghu; Sneha, Subramaniyan; Hemavathy, Nagarajan; Umashankar, Vetrivel; Jeyakanthan, Jeyaraman.
Afiliación
  • Rangaswamy R; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Tamil Nadu, Karaikudi, 630 003, India.
  • Sneha S; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Tamil Nadu, Karaikudi, 630 003, India.
  • Hemavathy N; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Tamil Nadu, Karaikudi, 630 003, India.
  • Umashankar V; Virology & Biotechnology/Bioinformatics Division, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, 600 031, India.
  • Jeyakanthan J; Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Tamil Nadu, Karaikudi, 630 003, India. jjbioinformatics@gmail.com.
Mol Divers ; 2024 Jul 06.
Article en En | MEDLINE | ID: mdl-38970640
ABSTRACT
Rheumatoid Arthritis (RA) is a chronic, symmetrical inflammatory autoimmune disorder characterized by painful, swollen synovitis and joint erosions, which can cause damage to bone and cartilage and be associated with progressive disability. Despite expanded treatment options, some patients still experience inadequate response or intolerable adverse effects. Consequently, the treatment options for RA remain quite limited. The enzyme AKT1 is crucial in designing drugs for various human diseases, supporting cellular functions like proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. Therefore, AKT serine/threonine kinase 1 is considered crucial for targeting therapeutic strategies aimed at mitigating RA mechanisms. In this context, directing efforts toward AKT1 represents an innovative approach to developing new anti-arthritis medications. The primary objective of this research is to prioritize AKT1 inhibitors using computational techniques such as molecular modeling and dynamics simulation (MDS) and shape-based virtual screening (SBVS). A combined SBVS approach was employed to predict potent inhibitors against AKT1 by screening a pool of compounds sourced from the ChemDiv and IMPPAT databases. From the SBVS results, only the top three compounds, ChemDiv_7266, ChemDiv_2796, and ChemDiv_9468, were subjected to stability analysis based on their high binding affinity and favorable ADME/Tox properties. The SBVS findings have revealed that critical residues, including Glu17, Gly37, Glu85, and Arg273, significantly contribute to the successful binding of the highest-ranked lead compounds at the active site of AKT1. This insight helps to understand the specific binding mechanism of these leads in inhibiting RA, facilitating the rational design of more effective therapeutic agents.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Divers Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Divers Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos