2D-quantitative structure–activity relationships model using PLS method for anti-malarial activities of anti-haemozoin compounds

• Published in: Malaria Journal
• Main Authors: Phuong Thuy Viet Nguyen, Truong Van Dat, Shusaku Mizukami, Duy Le Hoang Nguyen, Farhana Mosaddeque, Son Ngoc Kim, Duy Hoang Bao Nguyen, Oanh Thi Đinh, Tu Linh Vo, Giang Le Tra Nguyen, Cuong Quoc Duong, Satoshi Mizuta, Dao Ngoc Hien Tam, M. Phuong Truong, Nguyen Tien Huy, Kenji Hirayama
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2021
• Subjects: Antimalarial; Anti-haemozoin; In silico; Quantitative structure–activity relationship; QSAR; Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic
• Online Access: https://doi.org/10.1186/s12936-021-03775-2; https://doaj.org/article/aac7b51a222d491abe5ee9df5a026ff6

Abstract Background Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation. Methods With this in mind, this study developed two-dimensional-quantitative structure–activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers. Results Five two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in “ortho” position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity. Conclusions The model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this ...