Title:Pharmacophore Optimization using Pharmacophore Mapping, QSAR,
Docking, and ADMET Screening of Novel Pyrimidines Derivatives as
Anticancer DNA Inhibitors
Volume: 22
Issue: 1
Author(s): Shital M. Patil*, Vrushali Randive, Indrani Mahadik, Shashikant Bhandari, Kalyani Asgonkar and Piyush Nikalje
Affiliation:
- Department of Chemistry, AISSMS College of Pharmacy, Kennedy Road, Pune-01, India
Keywords:
3D QSAR, DNA inhibitor, N-alkyl bromide derivatives, Molecular docking, Pharmacophore mapping, ADME.
Abstract: Cancer is a global health issue, and cancer cells' resistance to existing treatments has
prompted a search for new anticancer drugs. The DNA of cancer cells is regarded as the primary
target for developing new molecules. In-silico studies aid in the optimization of current pharmacophores
and the development of new molecules. This study aimed to optimize the pharmacophore
utilizing QSAR studies and pharmacophore mapping to generate novel chemical entities (NCEs) of
pyrimidine derivatives as DNA inhibitors for cancer treatment. Furthermore, these NCEs were subjected
to molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity
(ADMET) screening to determine their drug-likeness. This study used Schrodinger's Maestro (13.4)
software for pharmacophore mapping, QSAR, molecular docking, and ADME. Toxicity was determined
using the Pro Tox II online tool. Pharmacophore mapping was performed using the phase
module. The QSAR model was generated using an atom-based QSAR approach. The Qik prop module
was utilized for ADME prediction. Molecular docking was done in Standard precision mode. In
pharmacophore mapping, we discovered that the DHHRR_1 hypothesis fitted best, with a survival
score of 5.4408. The optimal atom-based QSAR model produced correlation coefficients of R2 =
0.9487 and Q2 = 0.8361. Based on QSAR research, a new set of 43 derivatives was generated. These
compounds pass all ADMET requirements. In molecular docking investigations, three compounds
demonstrated binding with key amino acids with a significant dock score comparable to the standard.
Considering docking data and pharmacokinetic behavior of newly developed compounds, molecules
NC10, NC9, and NC43 have the highest DNA binding capability.
