Phytoflavonoids as alternative therapeutic effect for melanoma: Integrative Network pharmacology, molecular dynamics and drug-likeness profiling for lead discovery

Manoj Kumar Prajapati; Abhilasha Mittal; Pritipadma Panda

doi:10.1016/j.compbiolchem.2025.108390

Phytoflavonoids as alternative therapeutic effect for melanoma: Integrative Network pharmacology, molecular dynamics and drug-likeness profiling for lead discovery

Comput Biol Chem. 2025 Feb 21:117:108390. doi: 10.1016/j.compbiolchem.2025.108390. Online ahead of print.

Authors

Manoj Kumar Prajapati¹, Abhilasha Mittal², Pritipadma Panda³

Affiliations

¹ NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan 303121, India; Kashi Institute of Pharmacy, Mirzamurad, Varanasi, Uttar Pradesh 221307, India. Electronic address: prajapati.mpharm@gmail.com.
² NIMS Institute of Pharmacy, NIMS University, Jaipur, Rajasthan 303121, India.
³ School of Pharmacy, Kalinga Institute of Industrial Technology Deemed to be University, Patia, Bhubaneswar, Odisha 751024, India.

PMID: 40056707
DOI: 10.1016/j.compbiolchem.2025.108390

Abstract

Melanoma, an aggressive skin cancer, poses significant therapeutic challenges due to its resistance to conventional therapies and high metastatic potential. From this perspective, phytoflavonoids from different medicinal and aromatic plants gained attention due to their diverse multimodal anticancer effects with higher antioxidant and anti-inflammatory properties. This study explores phytoflavonoid potency against melanoma via a computer-aided drug design (CADD) platform. Using the core moiety of flavonoids (flavan), four most putative targets, such as cyclin-dependent kinases 1 and 5 (CDK1, CDK5), cell division cycles 25B and 225 C (CDC25B, and CDC225C), have been identified through a network pharmacology approach using TNMplot datasets (GenChip and RNA sequence). Further, 44 phytoflavonoids were selected from extensive literature, and molecular docking studies were carried out against four targets along with standard drugs using AutoDock 4.2 software. Subsequently, physicochemical, toxicity, pharmacokinetics, and drug-ability profiles of phytoflavonoids were predicted. Based on potency and drug-ability, we have selected 'CDK1-naringenin' with the standard drug complex, 'CDK1-dinaciclib,' for molecular dynamic simulation at 100 nanoseconds using GROMACS 2020 software. Based on potency (average docking score: 8.35 kcal/mol.), physicochemical properties (obeyed Lipinski rule of five), toxicity (class-IV), fifty percent lethal dose (2000 mg/kg), bioavailability (0.55), drug-likeness score (0.82), along with ideal pharmacokinetics profiles and higher protein-ligand stability, naringenin is considered as a potential and non-toxic anticancer candidate to be used for melanoma as alternative or complementary agent. The integrative and systematic analyses not only highlight the potential of phytoflavonoids but also select the potential lead from the library within limited resources to accelerate the current anticancer drug discovery process.

Keywords: Melanoma; Molecular docking and simulation; Network pharmacology; Phytoflavonoids; Toxicity and drug-ability profiles.