Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants

Abstract

Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively for treatment of Alzheimer's disease, Huntington's disease, glaucoma, and in hippocampal neurons from aged mice. However, phytochemicals have received far little attention in studies involving development of potential CYP46A1 inhibitors. Thus, in the present study phytoconstituents from Indian traditional medicinal plants; Bacopa monnieri, Piper longum, and Withania somnifera, were virtually screened for interaction with CYP46A1 using computational tools. Out of three plants, six molecules from P. longum and three molecules from W. somnifera were shortlisted to study interactions with CYP46A1 based on the physio-chemical parameters. Fargesin, piperolactam A and coumaperine from P. longum showed the higher binding affinity and the values were - 10.3, - 9.5, - 9.0 kcal/moles respectively, whereas, withaferin A from W. somnifera had a binding affinity of - 12.9 kcal/mol. These were selected as potential modulators as they exhibited suitable interactions with active site residues; Tyr109, Leu112, Trp368, Gly369, and Ala474. The selected molecules were further subjected to molecular dynamics simulation. Further, the pharmacological properties of molecules were also predicted using ADMET calculator and the data revealed that all the selected compounds had good absorption as well as solubility characteristics. In addition, sesamin, fargesin, piperolactam A, and coumaperine had minimal or no toxic effects. Thus, the study successfully identified compounds from Indian medicinal plants that may serve as potential inhibitors of CYP46A1 or base structures to design novel CYP46A1 inhibitors, which may be effective in treating neurological conditions involving perturbed cholesterol homeostasis.

Supplementary information: The online version contains supplementary material available at 10.1007/s42485-022-00098-x.

Keywords: Brain; Cholesterol; Cytochrome P450; In Silico; Lipids; Phytochemicals.

Fig. 1

a Validation of docking method by superimposition of co-crystal protein–ligand complex (ligand-red, chain A-green, heme-blue) over the docked conformation of the protein–ligand complex (ligand-aquamarine, chain A-yellow, heme-pink) b 3-dimensional structure of cholesterol 3-sulfate

Fig. 2

Steps in the selection of lead molecules

Fig. 3

2-dimensional and 3-dimensional interactions of clotrimazole with amino acid residues (cyan) at a particular bond distance in the pocket of protein CYP46A1 (silver). (atoms are coloured according to their type: carbon- orange, oxygen- red, nitrogen- blue; hydrogens are not shown)

Fig. 4

2-dimensional and 3-dimensional interactions of a Fargesin b Piperolactam A c Coumaperine (orange) with amino acid residues (cyan) at a particular bond distance in the pocket of CYP46A1 (silver). (atoms are coloured according to their type: carbon- orange, oxygen- red, nitrogen- blue; hydrogens are not shown)

Fig. 5

2-dimensional and 3-dimensional interactions of Withaferin A with amino acid residues (cyan) at a particular bond distance in the pocket of CYP46A1 (silver). (atoms are coloured according to their type: carbon- orange, oxygen- red, nitrogen- blue; hydrogens are not shown)

Fig. 6

Molecular dynamics trajectory analysis of the Clotrimazole-protein complex. a Protein–ligand RMSD; b RMSF for protein, green colored lines marked to indicate the residues which interacts with ligand; c Interaction of protein and ligand and d RMSF for ligand

Fig. 7

Contact Analysis of MD trajectory of Clotrimazole complex a Protein–ligand contact distribution histogram; b protein–ligand contacts

Fig. 8

Molecular dynamics trajectory analysis of the Coumaperine-protein complex. a Protein–ligand RMSD; b RMSF for protein, green colored lines marked to indicate the residues which interacts with ligand; c Interaction of protein and ligand and d RMSF for ligand

Fig. 9

Contact Analysis of MD trajectory of Coumaperine complex a Protein–ligand contact distribution histogram; b protein–ligand contacts

Fig. 10

Molecular dynamics trajectory analysis of the Fargesin-protein complex. a Protein–ligand RMSD; b RMSF for protein, green colored lines marked to indicate the residues that interacts with ligand; c Interactions of protein and ligand and d RMSF for ligand

Fig. 11

Contact Analysis of MD trajectory of Fargesin complex a Protein–ligand contact distribution histogram; b protein–ligand contacts

Fig. 12

Molecular dynamics trajectory analysis of the Piperolactam-protein complex. a Protein–ligand RMSD; b RMSF for protein, green colored lines marked to indicate the residues which interacts with ligand; c Interaction of protein and ligand and d RMSF for ligand

Fig. 13

Contact Analysis of MD trajectory of Piperolactam complex a Protein–ligand contact distribution histogram; b protein–ligand contact

Fig. 14

Molecular dynamics trajectory analysis of the Withferin-protein complex. a Protein–ligand RMSD; b RMSF for protein, green colored lines marked to indicate the residues which interacts with ligand; c Interaction of protein and ligand and d RMSF for ligand

Fig. 15

Contact Analysis of MD trajectory of Withferin complex a Protein–ligand contact distribution histogram; b protein–ligand contacts