In-silico Screening and Identification of Novel Trypanothione Reductase Inhibitor from Leishmania
Misbahuddin M. Rafeeq *
Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, 21589, KSA.
Ziaullah M. Sain
Department of Microbiology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, 21589, KSA.
Khwaja Mohd Amir
Department of Physiology, Basic Medical Sciences, College of Medicine, Majmaah University, Al-Majmaah 11952, Kingdom of Saudi Arabia.
Najat Binothman
Department of Chemistry, College of Science and Art, King Abdulaziz University, Rabigh, Saudi Arabia.
Majidah Aljadani
Department of Chemistry, College of Science and Art, King Abdulaziz University, Rabigh, Saudi Arabia.
Ahmad Alzamami
Clinical Laboratory Science Department, College of Applied Medical Science, Shaqra University, Saudi Arabia.
Norah A. Alturki
Clinical Laboratory Science Department, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia.
Abdulrahman Almutairi
Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), P.O.Box 22490, Riyadh, Saudi Arabia.
Rashed Ahmed Alniwaider
Toxicology Laboratory, Department of Pathology and Laboratory Medicine, Ministry of National Guard Hospital and Health Affairs (MNGHA), P.O.Box 22490, Saudi Arabia.
Ahmed Hamdan Aloufi
Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), P.O.Box 22490, Dammam, Saudi Arabia.
Alaa Hamed Habib
Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
*Author to whom correspondence should be addressed.
Abstract
The negative effects of leishmanicidal medications are numerous, and drug resistance to all of them has been observed. As a result, new medication development and the identification of novel therapeutic targets are critical. Leishmania major trypanothione reductase (Lm-TR), a NADPH-dependent flavoprotein oxidoreductase critical for thiol metabolism, is required for parasite viability. Since it lowers trypanothione, a chemical required by Leishmania's tryparedoxin/tryparedoxin peroxidase system to neutralise hydrogen peroxide (H2O2) produced by host macrophages during infection, this enzyme is essential for parasite survival in the host.
Because it is not found in the mammalian host, this enzyme is a promising target for novel anti-leishmania medicines. A three-dimensional model of Lm-TR was created using I-TASSER server. Virtual screening of about 5000 sigma aldrich compounds, acquired from the ZINC database, was carried out using Autodock vina tool. Top ten compounds were tabulated based on binding affinity.
The molecules with the ids ZINC04245710 and ZINC03869768 had the highest binding affinities of -11.4 and -11.2 kcal/mol, respectively. These compounds had the maximum binding affinity and the appropriate amount of hydrogen bonds. These molecules may be able to efficiently block the activity of the target enzyme (Lm-TR) and so serve as novel agents to combat cutaneous leishmaniasis. In search for new anti-Leishmania medications that are more effective and less cytotoxic, these molecules may provide a good starting point for a hit-to-lead procedure.
Keywords: Leishmania, parasite, virtual screening, cytotoxic, binding affinities