Discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as anticancer agents: virtual screening and molecular dynamic studies

Dhiman S., Gupta S., Kashaw S., Chtita S., BATIR G. G., Almehizia A., ...Daha Fazla

SAR and QSAR in Environmental Research, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1080/1062936x.2024.2432009
  • Dergi Adı: SAR and QSAR in Environmental Research
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Environment Index, MEDLINE, Pollution Abstracts, Veterinary Science Database
  • Anahtar Kelimeler: 3D-QSAR, CDK4 inhibitors, molecular dynamics simulation, pharmacophore mapping, virtual screening
  • Sivas Cumhuriyet Üniversitesi Adresli: Evet

Özet

CDK/Cyclins are dysregulated in several human cancers. Recent studies showed inhibition of CDK4/6 was responsible for controlling cell cycle progression and cancer cell growth. In the present study, atom-based and field-based 3D-QSAR, virtual screening, molecular docking and molecular dynamics studies were done for the development of novel pyrrolo[2,3-d]pyrimidine (P2P) derivatives as anticancer agents. The developed models showed good Q2 and r2 values for atom-based 3D-QSAR, which were equal to 0.7327 and 0.8939, whereas for field-based 3D-QSAR the values were 0.8552 and 0.6255, respectively. Molecular docking study showed good-binding interactions with amino acid residues such as VAL-101, HIE-100, ASP-104, ILE-19, LYS-147 and GLU-99, important for CDK4/6 inhibitory activity by using PDB ID: 5L2S. Pharmacophore hypothesis (HHHRR_1) was used in the screening of ZINC database. The top scored ZINC compound ZINC91325512 showed binding interactions with amino acid residues VAL-101, ILE-19, and LYS-147. Enumeration study revealed that the screened compound R1 showed binding interactions with VAL 101 and GLN 149 residues. Furthermore, the Molecular dynamic study showed compound R1, ZINC91325512 and ZINC04000264 having RMSD values of 1.649, 1.733 and 1.610 Å, respectively. These ZINC and enumerated compounds may be used for the development of novel pyrrolo[2,3-d]pyrimidine derivatives as anticancer agent.