Discovery of novel MLK4 inhibitors against colorectal cancer through computational approaches

Shopnil Akash; S K Hasibul Islam Shanto; Md Rezaul Islam; Imren Bayil; Samson Olusegun Afolabi; Abdelkrim Guendouzi; Magda H Abdellattif; Magdi E A Zaki

doi:10.1016/j.compbiomed.2024.109136

Discovery of novel MLK4 inhibitors against colorectal cancer through computational approaches

Comput Biol Med. 2024 Nov:182:109136. doi: 10.1016/j.compbiomed.2024.109136. Epub 2024 Sep 18.

Authors

Shopnil Akash¹, S K Hasibul Islam Shanto², Md Rezaul Islam³, Imren Bayil⁴, Samson Olusegun Afolabi⁵, Abdelkrim Guendouzi⁶, Magda H Abdellattif⁷, Magdi E A Zaki⁸

Affiliations

¹ Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh. Electronic address: [email protected].
² Department of Pharmacy, Faculty of Health Science, Northern University Bangladesh, Ashkona, Dhaka, 1230, Bangladesh. Electronic address: [email protected].
³ Department of Pharmacy, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh.
⁴ Department of Bioinformatics and Computational Biology, Gaziantep University, Turkey. Electronic address: [email protected].
⁵ Infochemistry Scientific Center, ITMO University, Saint Petersburg, 191002, Russia. Electronic address: [email protected].
⁶ Laboratory of Chemistry: Synthesis, Properties and Applications (LCSPA), University of Saïda, Algeria. Electronic address: [email protected].
⁷ Chemistry Department, College of Sciences, University College of Taraba, Taif University, Saudi Arabia. Electronic address: [email protected].
⁸ Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University Riyadh, Saudi Arabia. Electronic address: [email protected].

PMID: 39298888
DOI: 10.1016/j.compbiomed.2024.109136

Abstract

Colorectal cancer (CRC) is a significant health issue globally, affecting approximately 10 % of the world's population. The prevalence of CRC highlights the need for effective treatments and prevention strategies. The current therapeutic option, such as chemotherapy, has significant side effects. Thus, this study investigated the anticancer properties of Sanguinarine derivatives, an alkaloid found in traditional herbs via chemoinformatic approaches. Six Sanguinarine derivatives were discovered through virtual screening and molecular docking to determine their binding affinities against the mixed lineage kinase (MLK4) protein which is responsible for CRC. All the compounds were found to be more effective than standard drug used for colorectal cancer treatment, with Sanguinarine derivative 11 showing the highest affinity. The stability of the drug was confirmed through molecular dynamics simulations at 500 ns. This suggests that compound 11 has a higher chance of replacing 5-Fluorouracil, which is currently a widely used chemotherapy drug. Before molecular dynamics simulations, the pharmacokinetic and chemical properties of Sanguinarine derivatives were determined using pkCSM server and DFT method, respectively. The results support that compound 11 is a good drug candidate, as evidenced by Lipinski's Rule of Five. Therefore, compound 11 is recommended for further analysis via in vivo and in vitro studies to confirm its efficacy and safety.

Keywords: Colorectal cancer; Mixed lineage kinases; Molecular docking; Molecular dynamics simulation; Sanguinarine derivatives.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Benzophenanthridines / chemistry
Benzophenanthridines / pharmacology
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / metabolism
Drug Discovery
Humans
Isoquinolines* / chemistry
Isoquinolines* / pharmacology
Isoquinolines* / therapeutic use
Molecular Docking Simulation*
Molecular Dynamics Simulation
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology

Substances

Isoquinolines
Protein Kinase Inhibitors
sanguinarine
Benzophenanthridines
Antineoplastic Agents