Sains Malaysiana 52(10)(2023): 2855-2867
http://doi.org/10.17576/jsm-2023-5210-10
Revealing the Potency of
1,3,5-Trisubstituted Pyrazoline as Antimalaria through Combination of In Silico Studies
(Mendedahkan Potensi Pirazolin 1,3,5-Tritertukarganti sebagai Antimalaria melalui Gabungan Kajian in silico)
HERLINA
RASYID1,*, NUNUK HARIANI SOEKAMTO1,
SYADZA FIRDAUSIAH1,2, RISKA MARDIYANTI1, BAHRUN1,
SISWANTO3, MUHAMMAD ASWAD4, WAHYU DITA SAPUTRI5,
ARTANIA A. T. SUMA6, NUR HILAL SYAHRIR7 & RISNITA
VICKY LISTYARINI8,9
1Chemistry Department,
Faculty of Mathematics and Natural Sciences, Hasanuddin University, Makassar, South Sulawesi 90245, Indonesia
2Nano Life Science
Institute, Graduate School of Frontier Science Initiative, Kanazawa University,
Japan
3Department of
Statistics, Hasanuddin University, Makassar, South
Sulawesi 90245, Indonesia
4Faculty of Pharmacy, Hasanuddin University, Makassar, South Sulawesi 90245,
Indonesia
5Research Center for Quantum Physics, National Research and Innovation
Agency (BRIN), Habibie Science and Technology Complex (Puspiptek), Serpong 15314, South Tangerang, Indonesia
6Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Bulaksumur,
Yogyakarta, 55281, Indonesia
7Department of
Statistics, Faculty of Mathematics and Natural Sciences, Universitas Sulawesi Barat, Majene, 90311, Indonesia
8Theoretical Chemistry
Division, Institute of General, Inorganic and Theoretical Chemistry, University
of Innsbruck, Innrain 80-82A, A-6020 Innsbruck,
Austria
9Chemistry Education
Study Program, Sanata Dharma University, Yogyakarta
55282, Indonesia
Diserahkan: 31 Mei 2023/Diterima: 14 September
2023
Abstract
The potency of 1,3,5-trisubstituted pyrazoline as an antimalarial agent has been studied
through quantitative structure-activity relationship, molecular docking, and
molecular dynamics simulation as a combination of in silicostudies. The study commenced by
applying quantitative structure-activity relationship (QSAR) to 25 derivative
compounds using 3D-descriptor. The genetic algorithm and multiple linear
analysis were used to construct the QSAR model, which resulting an equation
that has Rtraining as 0.8100 and Rtest set as 0.9222. Descriptors involved in the QSAR equation
are TDB4 m, TDB8s, RDF30e, and RDF552, all of which belong to the group of 3D
autocorrelation and RDF. This result is in line with the principal
component analysis, which shows that both group descriptors represent whole 3D descriptors.
Molecular docking analysis is conducted to study the interaction between pyrazoline derivatives and the falcipain-2 enzyme.
Interactions between compound 14 and falcipain-2 is describing by
hydrogen bond against Glu14 amino acid residue, more pi-stacking interaction, and
van der Waals. Chloroquine as a positive control also presented one hydrogen
bond with Gly83, pi-sulfur against Cys42, and van der Waals. The stability of
the ligand–enzyme interaction is evaluated by molecular dynamics simulation, and
after 100 ns simulations, the root mean square deviation results show that
compound 14 and chloroquine have a stable interaction with the
falcipain-2 enzyme. Overall, this research provides the insight of
1,3,5-trisubstitued pyrazoline compounds as antimalaria by giving a QSAR equation and used to design a
better falcipain-2 inhibitors.
Keywords: Antimalaria; molecular docking; molecular dynamics simulation; QSAR; 1,3,5-trisubstituted pyrazoline
Abstrak
Potensi pirazolin 1,3,5-tritertukarganti sebagai agen antimalaria telah dikaji melalui hubungan struktur-aktiviti kuantitatif, dok molekul dan simulasi dinamik molekul sebagai gabungan kajian in silico. Kajian dimulakan dengan menggunakan hubungan struktur-aktiviti kuantitatif (QSAR) kepada 25 sebatian terbitan menggunakan petunjuk 3D. Algoritma genetik dan analisis linear berbilang telah digunakan untuk membina model QSAR yang menghasilkan persamaan yang mempunyai Rtraining sebagai 0.8100 dan Rtest set sebagai 0.9222. Petunjuk yang terlibat dalam persamaan QSAR ialah TDB4 m,
TDB8s, RDF30e dan RDF552 yang kesemuanya tergolong dalam kumpulan autokorelasi 3D dan RDF. Keputusan ini adalah selaras dengan analisis komponen utama yang menunjukkan bahawa kedua-dua petunjuk kumpulan mewakili keseluruhan petunjuk 3D. Analisis dok molekul dijalankan untuk mengkaji interaksi antara terbitan pirazolin dan enzim falcipain-2. Interaksi antara sebatian 14 dan falcipain-2 diterangkan dengan ikatan hidrogen terhadap residu asid amino Glu14, lebih banyak interaksi susun pi dan van der Waals. Klorokuin sebagai kawalan positif juga membentangkan suatu ikatan hidrogen dengan Gly83, pi-sulfur terhadap Cys42 dan van der Waals. Kestabilan interaksi ligan-enzim dinilai oleh simulasi dinamik molekul dan selepas simulasi 100 ns, hasil sisihan kuasa dua punca purata menunjukkan bahawa sebatian 14 dan klorokuin mempunyai interaksi yang stabil dengan enzim falcipain-2. Secara keseluruhannya, penyelidikan ini memberikan gambaran tentang sebatian pirazolin 1,3,5-tritertukarganti sebagai antimalaria dengan memberikan persamaan QSAR dan digunakan untuk mereka bentuk perencat falcipain-2 yang lebih baik.
Kata kunci: Antimalaria; dok molekul; QSAR; pirazolina 1,3,5-tritertukarganti; simulasi dinamik molekul
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*Pengarang untuk surat-menyurat; email: herlinarasyid@unhas.ac.id
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