Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions

Abstract

Drug resistance acquired by Leishmania donovani (Ldv) is a major problem in the treatment and control of visceral leishmaniasis (VL). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme has been targeted as is found in other protozoan which cause diseases like sleeping sickness. GAPDH gene of Ldv (AG83 strain) was amplified, sequenced, and modeled on the basis of crystal structure of Leishmania mexicana. The model of the Ldv GAPDH exhibited NAD-binding domain with Rossmann folding. Virtual screening of different experimentally proved compounds with the crystal and the modeled structures of GAPDH of Leishmania strains revealed diverse binding affinities of different compounds. Comparison of binding affinities (based on different programs) of compounds revealed that discovery studio v2.5 (Ligandfit) was able to predict the most hit compounds, the best hit compounds against GAPDH of Leishmania strains are hydrazine, vetrazine, and benzyl carbazate. It is predicted that patients suffering from both VL and cardiac disorders (atrial fibrillation) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome.

Keywords:

• homology modeling
• GAPDH
• Leishmania
• VL
• hydrazine
• vetrazine
• benzyl carbazate
• warfarin

Acknowledgments

This study was supported by a grant for setting up a biomedical informatics centre from Indian Council of Medical Research (ICMR), Govt. of India. We acknowledge Rishikesh Kumar, Anurag Singh Chauhan, Kumar Gaurav, and Sabina Yasmin for their suggestions in the preparation of the manuscript. We thank Dr Meera Singh, Dr S.K. Dey Biswas, and Dr Harpreet Singh, Scientists of ICMR, New Delhi for helping us in setting up our Biomedical Informatics Centre in RMRIMS, Patna, India.