Investigation of cathinone analogs targeting human dopamine transporter using molecular modeling

Abstract

In a step towards understanding the structure–property relationship among Synthetic Cathinones (SCs), a combined methodology based on Density Functional Theory (DFT), Administration, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions, docking and molecular dynamics simulations have been applied to correlate physicochemical descriptors of various SCs to their biological activity. The results from DFT and molecular docking studies correlate well with each other explaining the biological activity trends of the studied SCs. Quantum mechanical descriptors viz. polarizability, electron affinity, ionization potential, chemical hardness, electronegativity, molecular electrostatic potential, and ion interaction studies unravel the distinguishingly reactive nature of Group D (pyrrolidine substituted) and Group E (methylenedioxy and pyrrolidine substituted) compounds. According to ADMET analysis, Group D and Group E molecules have a higher probability of permeating through the blood–brain barrier. Molecular docking results indicate that Phe76, Ala77, Asp79, Val152, Tyr156, Phe320, and Phe326 constitute the binding pocket residues of hDAT in which the most active ligands MDPV, MDPBP, and MDPPP are bound. Finally, to validate the derived quantum chemical descriptors and docking results, Molecular Dynamics (MD) simulations are performed with homology-modelled hDAT (human dopamine transporter). The MD simulation results revealed that the majority of SCs remain stable within the hDAT protein’s active sites via non-bonded interactions after 100 ns long simulations. The findings from DFT, ADMET analysis, molecular docking, and molecular dynamics simulation studies complement each other suggesting that pyrrolidine-substituted SCs (Group D and E), specifically, MPBP and PVN are proven potent SCs along with MDPV, validating various experimental observations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Synthetic cathinone
• DFT
• docking
• hDAT
• MDPV

Acknowledgments

B. R. S. acknowledges UGC for SRF (Senior Research Fellowship) funding, B. R. S., and K. J. acknowledges Center of Excellence in Scientific Computing (COESC) at CSIR-National Chemical Laboratory (NCL), Pune, and PARAM Brahma Facility under the National Supercomputing Mission, Government of India at the Indian Institute of Science Education and Research Pune for providing high-performance computing facilities. S.K. and K.J. acknowledges the Hydrogen Mission Mode Project (H2T mission) -Development of Electrolyser Technology for Affordable Generation of Hydrogen 16(DELTAGH) (Project Code: HCP44-08) under National Hydrogen EnergyMission sponsored by the Council of Scientific & Industrial Research.

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No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.