Molecular Modeling and Dynamics Simulation Analysis of KATNAL1 for Identification of Novel Inhibitor of Sperm Maturation

Author(s): Kishore Sarma, Shubhadeep Roychoudhury, Sudipta Sankar Bora, Budheswar Dehury, Pratap Parida, Saurav Das, Robin Das, Chandrajit Dohutia, Sangeeta Nath, Bibhas Deb, Mahendra K Modi.

Journal Name: Combinatorial Chemistry & High Throughput Screening

Volume 20 , Issue 1 , 2017

Abstract:

Background: Hormone based birth control often causes various side effects. A recent study revealed that temporary infertility without changing hormone levels can be attained by inhibiting Katanin p60 ATPase-containing subunit A-like 1 protein (KATNAL1) which is critical for sperm maturation in the testes.

Objective: This study aimed at attaining the most energetically stable three dimensional (3D) structure of KATNAL1 protein using comparative modeling followed by screening of a ligand library of known natural spermicidal compounds for their binding affinity with KATNAL1. This in turn may inhibit the development of mature sperm in the seminiferous epithelium.

Method: A series of computational techniques were used for building the 3D structure of KATNAL1 which was further optimized by molecular dynamics (MD) simulation. For revealing the ATP binding mode of KATNAL1, docking study was carried out using the optimized model obtained from the MD simulation. The docking study was also employed to test the binding efficiency of the ligand library.

Results: Molecular docking study confirmed the ATP binding of KATNAL1 with various hydrophobic and hydrogen bond interactions. Binding efficiency of the ligand library suggested that calotropin, a cardenolide of Calotropis procera showed the highest binding efficiency against the target protein without toxicity. MD simulation of the docked complex validated the results of the docking study.

Conclusion: This study revealed the ATP binding mode of KATNAL1 and identified calotropin as a potential lead molecule against it showing high binding efficiency with good bioavailability and no mutagenicity. Further in vitro and in vivo bioassay of calotropin could facilitate the development of novel non-hormonal male-specific contraceptive in near future.

Keywords: KATNAL1, sperm maturation, non-hormonal contraceptive, homology modeling, docking, molecular dynamics simulation.

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Article Details

VOLUME: 20
ISSUE: 1
Year: 2017
Page: [82 - 92]
Pages: 11
DOI: 10.2174/1386207320666170116120104
Price: $58

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