Sains Malaysiana 45(7)(2016): 1113–1120

Inhibitors of Leishmania mexicana Phosphoglycerate Mutase Identified by Virtual

Screening and Verified by Inhibition Studies

(Pengenalpastian Perencat Fosfogliserat Mutase daripada Leishmania mexicana melalui Saringan Maya dan Pengesahannya menerusi Kajian Perencatan)

FAZIA ADYANI AHMAD FUAD¹*, DOUGLAS R. HOUSTON², PAUL A.M. MICHELS²,

LINDA A. FOTHERGILL-GILMORE² & MALCOLM D. WALKINSHAW²

¹Department of Biotechnology Engineering, Faculty of Engineering, International Islamic University Malaysia, 50728 Gombak, Kuala Lumpur, Malaysia

²Centre for Transitional and Chemical Biology, Institute of Quantitative Biology, Biochemistry and Biotechnology, The University of Edinburgh, The King’s Buildings, Edinburgh EH9 3BF, United Kingdom

Diserahkan: 10 September 2015/Diterima: 11 Februari 2016

ABSTRACT

Cofactor-independent phosphoglycerate mutase has been proposed as a therapeutic target for the treatment of trypanosomatid diseases. In this paper, we report the identification of compounds that could potentially be developed as selective inhibitors of cofactor-independent phosphoglycerate mutase from Leishmania mexicana (LmiPGAM). Virtual screening was used in this search, as well as compounds identified by high-throughput screening. A ligand-based virtual screen programme, ultra fast shape recognition with atom types (UFSRAT), was used to screen for compounds resembling the substrate/product, before a structure-based approach was applied using AutoDock 4 and AutoDock Vina in a consensus docking scheme. In this way eight selected compounds were identified. In addition, three compounds from the Library of Pharmacologically Active Compounds (LOPAC) were selected from the published results of high-throughput screening of this library. The inhibitory effects of these compounds were tested at a fixed concentration of 1 mM. The results showed that seven compounds inhibited LmiPGAM activity and of these, two compounds (one each from high-throughput and virtual screening) showed substantial inhibition (i.e. 14% and 49% remaining activity, respectively). Taken together, the findings from this study indicate that these compounds have potential as novel inhibitors that specifically target LmiPGAM.

Keywords: Cofactor-independent phosphoglycerate mutase; glycolysis; Leishmania mexicana; virtual screening analyses

ABSTRAK

Fosfogliserat mutase bebas-kofaktor telah dicadangkan sebagai sasaran terapeutik bagi penyakit yang disebabkan oleh tripanosomatida. Di sini kami melaporkan pengenalpastian sebatian yang berpotensi untuk dibangunkan sebagai perencat kepada fosfogliserat mutase bebas-kofaktor daripada Leishmania mexicana (LmiPGAM). Saringan secara maya telah diaplikasikan dalam kajian ini, selain daripada beberapa jenis sebatian yang dikenalpasti melalui saringan berprosesan tinggi. Program saringan maya berasaskan ligan, Ultra Fast Shape Recognition with Atom Types (UFSRAT), telah digunakan untuk menyaring sebatian yang menyerupai substrat/produk, sebelum pendekatan berasaskan struktur digunakan menerusi program AutoDock 4 dan AutoDock Vina di dalam skim simulasi pengikatan ligan kepada reseptor (docking) yang konsensus. Melalui kaedah ini, lapan sebatian terpilih telah dikenal pasti. Selain daripada itu, tiga sebatian daripada Library of Pharmacologically Active Compounds (LOPAC) yang dikenal pasti melalui kaedah saringan berprosesan tinggi terhadap perpustakaan ini yang telah diterbitkan turut dipilih untuk analisis lanjutan. Kesan perencatan kesemua sebatian ini telah diuji pada kepekatan yang ditetapkan pada 1 mM. Hasil analisis ini telah menunjukkan bahawa tujuh sebatian merencat aktiviti LmiPGAM, dengan dua sebatian (masing-masing daripada saringan berprosesan tinggi dan maya) menunjukkan perencatan yang ketara (14% dan 49% baki aktiviti). Secara keseluruhannya, hasil daripada kajian ini menunjukkan bahawa sebatian ini berpotensi sebagai perencat novel yang spesifik kepada LmiPGAM.

Kata kunci: Analisis saringan maya; fosfogliserat mutase bebas-kofaktor; glikolisis; Leishmania Mexicana

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*Pengarang untuk surat-menyurat; email: fazia_adyani@iium.edu.my