title: Multilevel Precision-Based Rational Design of Chemical Inhibitors Targeting the Hydrophobic Cleft of Toxoplasma gondii Apical Membrane Antigen 1 (AMA1).
abstract: Toxoplasma gondii is an intracellular Apicomplexan parasite and a causative agent of toxoplasmosis in human. It causes encephalitis, uveitis, chorioretinitis, and congenital infection. T. gondii invades the host cell by forming a moving junction (MJ) complex. This complex formation is initiated by intermolecular interactions between the two secretory parasitic proteins-namely, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) and is critically essential for the host invasion process. By this study, we propose two potential leads, NSC95522 and NSC179676 that can efficiently target the AMA1 hydrophobic cleft, which is a hotspot for targeting MJ complex formation. The proposed leads are the result of an exhaustive conformational search-based virtual screen with multilevel precision scoring of the docking affinities. These two compounds surpassed all the precision levels of docking and also the stringent post docking and cumulative molecular dynamics evaluations. Moreover, the backbone flexibility of hotspot residues in the hydrophobic cleft, which has been previously reported to be essential for accommodative binding of RON2 to AMA1, was also highly perturbed by these compounds. Furthermore, binding free energy calculations of these two compounds also revealed a significant affinity to AMA1. Machine learning approaches also predicted these two compounds to possess more relevant activities. Hence, these two leads, NSC95522 and NSC179676, may prove to be potential inhibitors targeting AMA1-RON2 complex formation towards combating toxoplasmosis.
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Vetrivel
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Muralikumar
authors.affiliation: L&T Microbiology Research Centre, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: B
authors.initials: B
authors.lastname: Mahalakshmi
authors.affiliation: L&T Microbiology Research Centre, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: K
authors.initials: K
authors.lastname: Lily Therese
authors.affiliation: L&T Microbiology Research Centre, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: H N
authors.initials: HN
authors.lastname: Madhavan
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Alameen
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai 600-006, India.
authors.forename: Indhuja
authors.initials: I
authors.lastname: Thirumudi
keywords: apical membrane antigen 1; drug design; hydrophobic interaction; molecular docking analyses; rhoptry neck protein 2; toxoplasmosis