Homology modelling and molecular docking studies of human placental cadherin protein for its role in teratogenic effects of anti-epileptic drugs. (February 2016)

• Record Type: Journal Article
• Authors: Piplani, Sakshi; Saini, Vandana; Niraj, Ravi Ranjan K.; Pushp, Adya; Kumar, Ajit
• Is Part Of: Computational biology and chemistry. Volume 60(2016)
• Page Start: 1
• Page End: 8
• Publication Date: 2016-02
• Subjects: AEDs anti-epileptic drugs -- AMBER assisted model building with energy refinement -- GUI graphical user interface -- GROMOS GROningen molecular simulation -- VPA valproic acid -- MD molecular dynamics; Cadherin -- AEDs -- Docking -- MD simulation -- Homology Modelling -- Teratogenicity; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2015.11.003
• Languages: English
• ISSNs: 1476-9271

Abstract

Graphical abstract: Highlights: Teratogenic effects of AEDs is predicted to be elevated when the pregnant woman is subjected to Ca-rich diet or Ca-supplements. hp-Cadherin is involved in teratogenic effects caused by 04 major marketed AEDs- Gabapentin, Pregabalin, Remacimide and Vigabatrin. hp-Cadherin is observed to have negligible role in the teratogenic effects of VPA. The major binding pockets for AEDs in hp-cadherin are, in general composed of charged, polar and aliphatic amino acids like Isoleucine, Tyrosine, Glutamate etc. Observation beckons a novel biochemical link of AEDs teratogenicity with placental cadherin and invites further investigation. Abstract: Anti-epileptic drugs (AEDs) have high risk of teratogenic side effects, including neural tube defects while mother is on AEDs for her own prevention of convulsions during pregnancy. The present study investigated the interaction of major marketed AEDs and human placental (hp)-cadherin protein, in-silico, to establish the role of hp-cadherin protein in teratogenicity and also to evaluate the importance of Ca 2+ ion in functioning of the protein. A set of 21 major marketed AEDs were selected for the study and 3D-structure of hp-cadherin was constructed using homology modelling and energy minimized using MD simulations. Molecular docking studies were carried out using selected AEDs as ligand with hp-cadherin (free and bound Ca 2+ ion) to study the behavioural changes in hp-cadherin due to presence of Ca 2+ ion. The study reflected that four AEDs (Gabapentin, Pregabalin, Remacimide and Vigabatrine) had very high affinity towards hp-cadherin and thus the later may have prominent role in the teratogenic effects of these AEDs. From docking simulation analysis it was observed that Ca 2+ ion is required to make hp-cadherin energetically favourable and sterically functional.