Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach

Ossama Daoui; Souad Elkhattabi; Mohamed Bakhouch; Salah Belaidi; Richie R Bhandare; Afzal B Shaik; Suraj N Mali; Samir Chtita

doi:10.1021/acsomega.2c07585

Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach

ACS Omega. 2023 Jan 19;8(4):4294-4319. doi: 10.1021/acsomega.2c07585. eCollection 2023 Jan 31.

Authors

Ossama Daoui¹, Souad Elkhattabi¹, Mohamed Bakhouch², Salah Belaidi³, Richie R Bhandare^{4

5}, Afzal B Shaik⁶, Suraj N Mali⁷, Samir Chtita⁸

Affiliations

¹ Laboratory of Engineering, Systems and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, BP Box 72, Fez30000, Morocco.
² Laboratory of Bioorganic Chemistry, Department of Chemistry, Faculty of Sciences, Chouaïb Doukkali University, P.O. Box 24, 24000El Jadida, Morocco.
³ Group of Computational and Medicinal Chemistry, LMCE Laboratory, University of Biskra, BP 145, Biskra707000, Algeria.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Ajman University, Ajman346, United Arab Emirates.
⁵ Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman P.O. Box 340, 346, United Arab Emirates.
⁶ St. Mary's College of Pharmacy, St. Mary's Group of Institutions Guntur, Affiliated to Jawaharlal Nehru Technological University Kakinada, Chebrolu, Guntur, Andhra Pradesh522212, India.
⁷ Department of Pharmacy, Government College of Pharmacy, Karad, Affiliated to Shivaji University, Kolhapur, Maharashtra415124, India.
⁸ Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Casablanca7955, Morocco.

Abstract

The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokinetic/pharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound 6d is identified as the optimal scaffold for drug design based on in silico screening tests. The computer-aided modeling developed in this study allowed us to design, optimize, and screen a new class of 36 small molecules based on cyclohexane-1,3-dione as potential c-Met inhibitors against NSCLC cell growth. The in silico rational drug design approach used in this study led to the identification of nine lead compounds for NSCLC therapy via c-Met protein targeting. Finally, the findings are validated using a 100 ns series of molecular dynamics simulations in an aqueous environment on c-Met free and complexed with samples of the proposed lead compounds and Foretinib drug.