A Computer - Aided Drug Designing for Pharmacological Inhibition of Mutant ALK for the Treatment of Non-small Cell Lung Cancer

Author(s): Saphy Sharda , Ravina Khandelwal , Ritu Adhikary , Diksha Sharma , Manisha Majhi , Tajamul Hussain , Anuraj Nayarisseri* , Sanjeev Kumar Singh* .

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 13 , 2019

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Graphical Abstract:


Abstract:

Background: Lung cancer is the most common among all the types of cancer worldwide with 1.8 million people diagnosed every year, leading to 1.6 million deaths every year according to the American cancer society. The involvement of mutated Anaplasic Lymphoma Kinase (ALK) positive fusion protein in the progression of NSCLC has made a propitious target to inhibit and treat NSCLC. In the present study, the main motif is to screen the most effective inhibitor against ALK protein with the potential pharmacological profile. The ligands selected were docked with Molegro Virtual Docker (MVD) and CEP-37440 (PubChem CID- 71721648) was the best docked pre-established compound with a permissible pharmacological profile.

Methods: The selected ligands were docked with Molegro Virtual Docker (MVD). With reference to the obtained compound with the lowest re-rank score, PubChem database was virtually screened to retrieve a large set of similar compounds which were docked to find the compound with higher affinity. Further comparative studies and in silico prediction included pharmacophore studies, proximity energy parameters, ADMET and BOILED-egg plot analysis.

Results: CEP-37440 (PubChem CID- 71721648) was the best docked pre-established compound with preferable pharmacological profile and PubChem compound CID-123449015 came out as the most efficient virtually screened inhibitor. Interestingly, the contours of the virtual screened compound PubChem CID- 123449015 fall within our desired high volume cavity of protein having admirable property to control the ALK regulation to prevent carcinogenesis in NSCLC. BOILED-Egg plot analysis depicts that both the compounds have analogous characteristics in the divergent aspects. Moreover, in the evaluations of Blood Brain Barrier, Human Intestinal Absorption, AMES toxicity, and LD50, the virtually screened compound (PubChem CID-123449015) was found within high optimization.

Conclusion: These investigations denote that the virtually screened compound (PubChem CID- 123449015) is more efficient to be a better prospective candidate for NSCLC treatment having good pharmacological profile than the pre-established compound CEP-37440 (PubChem CID- 71721648) with low re-rank score. The identified virtually screened compound has high potential to act as an ALK inhibitor and can show promising results in the research of non-small cell lung cancer (NSCLC).

Keywords: Non-small cell lung cancer (NSCLC), Anaplastic Lymphoma Kinase, ADMET, Molecular Docking, Virtual Screened, BOILED-Egg plot.

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VOLUME: 19
ISSUE: 13
Year: 2019
Page: [1129 - 1144]
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DOI: 10.2174/1568026619666190521084941
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