In Vol-03, Issue-02

Md. Shimul Bhuia 1, Abul Bashar Ripon Khalipha 1, 2*, Milon Mondal 1, Md. Solayman Hossain 1, Musfiqur Rahman Sakib 1, Abdullah Al Shamsh Prottay 1, Naimur Rahman 1, Md. Imran Hossain 1, Khadija Akter 1, Md. Sajjad Hossain Siam 1, Md. Hasibur Rahman 1

  1. Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman
    Science and Technology University, Gopalganj 8100, Bangladesh
  2. Evergreen Scientific Research Centre, Gopalganj 8100, Bangladesh

Alectinib (D) is an inhibitor of anaplastic lymphoma kinase (ALK) and approved by the USFDA for the treatment of non-small cell lung cancer (NSCLC). This study aims to develop & design new Alectinib derivatives which can be capable to inhibit more potently the activity of kinases other than ALK and better in pharmacokinetics than the parent drug in the treatment of NSCLC. The derivatives of Alectinib have been designed by using density functional theory (DFT) and the inhibitory performance of drugs was also
explored by molecular docking study. We have investigated frontier molecular orbital features (HOMO, LUMO, gap, hardness, and softness), electrostatic potential, dipole moment and thermodynamic properties (electronic energy,
enthalpy, Gibb’s free energy) of all the optimized drugs. The screening of the designed drugs (D-F, D-Cl, D-Br, D-CF3, D-OCH3, D-NH2) has been performed against ALK, RET, KDR, and KIT crystal structure of proteins. In our findings, the modified derivatives D-F and D-Cl revealed higher binding affinity -11.2 & -11.1 against ALK (PDB ID: 4TT7) respectively, where the
parent drug showed binding affinity -10 against the same protein. The pharmacokinetic properties & toxicity of all drugs were predicted by
preADMET, admetSAR@LMMD online database and MedChem designer. It assured that all the drugs are thermodynamically stable; some of them are more chemically reactive. In our computational investigation, we found that D-F & D-Cl are more potent inhibitors against ALK for the treatment of NSCLC than the parent drug. Finally, this study can be helpful for the design and development of new ALK inhibitors.

Keywords: Lung cancer, Alectinib, ALK, Virtual screening, NSCLC

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