In silico investigation of ketamine and methylphenidate drug-drug conjugate for MDD and ADHD treatment using MD simulations and MMGBSA

A computer-designed conjugate of ketamine and methylphenidate shows promise as a potential drug for both major depressive disorder and attention-deficit hyperactivity disorder. The conjugate was designed in ChemDraw and evaluated using computational tools for drug-likeness, toxicity, and binding to the target protein tryptophan hydroxylase 2 (TPH2). Molecular docking revealed the conjugate had a stronger binding affinity (−8.5 Kcal/mol) to TPH2 compared to ketamine alone (−6.7 Kcal/mol) or methylphenidate alone (−6.9 Kcal/mol). The conjugate was predicted to cross the blood-brain barrier, be non-toxic, and form stable interactions with TPH2, suggesting it is a safe candidate for enzyme-based therapeutics.

Study at a glance

Abstract

Major depressive disorder (MDD) and Attention-deficit hyperactivity disorder (ADHD) are pervasive psychiatric disorders characterized by impaired memory, sustained attention/motivation, and depression. FDA-approved Ketamine is an antidepressant drug but it affects cognitive abilities. Methylphenidate is the drug used for the treatment of ADHD. Chronic treatment overcomes attention and mental problems but causes depression. In the current study, we have made ketamine-methylphenidate conjugate to treat/reduce side effects to treat both MDD and ADHD. Ketamine and Methylphenidate conjugate were made by ChemDraw, tested for drug-likeness by Swiss ADME, and toxicity by toxCSM. Target gene in ADHD and MDD was selected by the KEGG database. Protein networking was performed by string. The target gene protein 3D structure was retrieved from RSCB-PDB and validated using the Ramachandran plot. Afterward, the active site was discovered by the deep site to perform molecular docking by Autodoc Vina and MD Simulation and MMGBSA by Desmond. Conjugate can cross the blood-brain barrier and shows drug-like properties. It was found to be non-toxic with very low probability prediction for various conditions. By the KEGG pathway, we selected our target protein Tryptophane hydroxylase 2 (TPH2). By molecular docking, conjugate showed good affinity towards TPH2 (− 8.5 Kcal/mol) as compared to Ketamine (− 6.7 Kcal/mol) and Methylphenidate (− 6.9 Kcal/mol). Hydrogen bonding and hydrophobic interactions stabilize the conjugate and TPH2 binding at the site and favor binding affinity and drug efficacy. Ketamine-methylphenidate conjugate is a potential drug candidate for enzyme-based therapeutics for MDD and ADHD. It is safe to use according to the in-silico CADD approach with sustained stability of TPH2.