Prospecting for new catechol--methyltransferase (COMT) inhibitors as a potential treatment for Parkinson's disease: a study by molecular dynamics and structure-based virtual screening.

Parkinson's disease (PD) is a neurodegenerative, chronic, and progressive disease, common in the elderly. The catechol--methyltransferase (COMT) is a monomeric enzyme involved in dopamine (DA) degradation, the neurotransmitter in deficit in patients with PD. The reference treatment of PD consists of levodopa (L-dopa) administration, which is the precursor of DA. The inhibition of COMT is an adjuvant treatment in PD since it keeps DA levels constant. The goal of this study was to identify drug candidates capable of inhibiting COMT for the treatment of PD and identify important fragments of these molecules. Initially, we analyzed the flexibility of COMT and defined its main conformations in solution regarding the absence (system I) and presence of the -adenosyl--methionine (SAM) cofactor (system II) through molecular dynamics (MD) simulations. Two regions in these structures were selected for molecular docking, firstly the entire cavity where the cofactor and substrates are bound and secondly the specific biding region of the enzyme substrates. Based on the conformations of the MD, the virtual screening (VS) was performed against FDA Approved and Zinc Natural Products databases aiming at the selection of the best compounds. Subsequently, the absorption, distribution, metabolization, excretion, and toxicity (ADMET) properties, as well as drug-score and drug-likeness indexes of the most promising compounds were analyzed. After a detailed analysis of the compounds selected by structure-based VS, it was possible to highlight the fragments most frequently involved in their stability: 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 9H-Benz(c)indole(3,2,1-ij)(1,5)naphthyridin-9-one and (10,13)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17dodecahydrocyclopenta[a]phenanthren-3-one. The identification of these potential fragments is essential for the prospection of more specific inhibitors against COMT using the technique of Fragment-based lead discovery (FBLD). Besides, this study allowed us to identify the potential COMT inhibitors through a complete understanding of molecular-level interactions based on the flexibility of this protein.Communicated by Ramaswamy H. Sarma.