The effect of mutation in vkorc1 on anticoagulant activity of warfarin
Alok Mishra1, Manoj Kumar Yadav2, Krishna kumar Ojha3, Sunil Kumar Srivastava4*
1 Department of Applied Science, Institute of engineering and technology, Lucknow
2 Bioinformatics, SRM University, Delhi-NCR, Sonepat
3 Department of Physics, Central University of South Bihar, Patna
4 Department of Physics, Mahatma Gandhi Central University Bihar, Motihari
* Corresponding Authors E-mail: sksrivastava[at]mgcub.ac.in
In humans, vitamin K epoxide reductase complex, subunit 1 named as vkorc1 by HUGO gene nomenclature committee (HGNC). vkorc1 is present on short arm of homo sapiens chromosome number 16 at position 11.2 from centromere. The nucleotide length is 4,102 from 31102175 to 31106276 on negative strand (1). We have taken the bacterial homologue of this gene because its structure is solved (2). The product of this gene encodes an enzyme which reduce vitamin K 2,3-epoxide to active form which is essential for blood clotting.
Warfarin (3) inhibits the vitamin K dependent synthesis of biologically active forms of the calcium dependent clotting factors II, VII. IX and X, as well as the regulatory factors protein C, protein S, and protein Z. We want to do the theoretical investigation of interaction of warfarin with VKORC1 protein. For this first we predicted the 3-D structure of VKORC1 using Ab Initio approach and then docked the warfarin with predicted VKORC1 protein structure using Auto Dock software. After taking the help of docking results, we have done the density functional quantum chemical calculation for ligand (warfarin) with amino acids present at the active sites of receptor (VKORC1) and analyzed the effect of mutation in vkorc1 on warfarin action of anticoagulation.
References:
1. Anonymous (VKORC1 vitamin K epoxide reductase complex, subunit 1 [ Homo sapiens (human) ]. ( 8600 Rockville Pike, Bethesda MD, 20894 USA ).
2. Li W, et al. (2010) Structure of a bacterial homologue of vitamin K epoxide reductase. (Translated from eng) Nature 463(7280):507-512 (in eng).
3. Mishra A, Srivastava SK, & Swati D (2013) Study of structure-activity relationship of enantiomeric, protonated and deprotonated forms of warfarin via vibrational spectroscopy and DFT calculations. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy.