Sains Malaysiana 52(10)(2023): 2855-2567

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 RASYID^1,*, NUNUK HARIANI SOEKAMTO¹, SYADZA FIRDAUSIAH^1,2, RISKA MARDIYANTI¹, BAHRUN¹, SISWANTO³, MUHAMMAD ASWAD⁴, WAHYU DITA SAPUTRI⁵, ARTANIA A. T. SUMA⁶, NUR HILAL SYAHRIR⁷ & RISNITA VICKY LISTYARINI^8,9

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

Received: 31 May 2023/Accepted: 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 regression analysis were used to construct the QSAR model, which resulting an equation that has R_training as 0.8100 and R_{test 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 R_training sebagai 0.8100 dan R_{test 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 sebatian14 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 sebatian14 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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*Corresponding author; email: herlinarasyid@unhas.ac.id