Homology Modeling of Leishmanolysin (gp63) from Leishmania panamensis and Molecular Docking of Flavonoids

Abstract

Leishmaniasis is a chronic disease caused by protozoa of the distinct Leishmania genus transmitted by sandflies of the genus Phlebotomus (old world) and Lutzomyia (new world). Among the molecular factors that contribute to the virulence and pathogenesis of Leishmania are metalloproteases, e.g., glycoprotein 63 (gp63), also known as leishmanolysin or major surface protease (MSP). This protease is a zinc-dependent metalloprotease that is found on the surface of the parasite, abundant in Leishmania promastigote and amastigote. This study describes the prediction of three-dimensional (3D) structures of leishmanolysin (UniProt ID A0A088RJX7) of Leishmania panamensis employing a homology modeling approach. The 3D structure prediction was performed using the SWISS-MODEL web server. The tools PROCHECK, Molprobyty, and Verify3D were used to check the quality of the model, indicating that they are reliable. Best docking configurations were identified applying AutoDock Vina in PyRx 0.8 to obtain a potential antileishmanial activity. Biflavonoids such as lanaroflavone, podocarpusflavone A, amentoflavone, and podocarpusflavone B showed good scores among these molecules. Lanaroflavone appears to be the most suitable compound from binding affinity calculations.

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

“…Moreover, MMP-2 and MMP-9 may not be the only metalloproteinases targeted by HNK and other biflavonoids. Recently, it has been proposed, based on an in silico docking study, that lanaroflavone, podocarpusflavone and amentoflavone can bind to the surface metalloprotease leishmanolysin (glycoprotein 63), implicated in the pathogenesis of Leishmania [ 79 ].…”

“…With more than 200 biflavonoids identified to date, it is not possible to summarize the biological properties of all compounds but, to complete the review, it is useful to refer to the anticancer properties of selected HNK-like compounds with a C–O–C linkage. Lanaroflavone B is an anti-inflammatory biflavonoid and the formation of stable complexes with human neutrophil elastase has been proposed, based on molecular modeling [ 104 ], in addition to the aforementioned binding to leishmanolysin [ 79 ]. Ochnaflavone is also an anti-inflammatory agent with a dual cyclooxygenase-2/5-lipoxygenase inhibitory activity [ 105 ] but it can also inhibit other enzymes such as phospholipase A2 [ 106 ] and suppresses lymphocyte proliferation [ 107 ].…”

Discovery of Alternative Chemotherapy Options for Leishmaniasis through Computational Studies of Asteraceae

“…Ogungbe et al [48] phosphoglucose isomerase, 1Q50 [88] , 1T10 [88] 2.60, 2.35 Ogungbe et al [48] pyruvate kinase, 1PKL, [89] 3HQP, [90] 3PP7 [91] 2.35, 2.30, 2.35 Ogungbe et al [48] phosphomannomutase, 2I54, [92] 2I55 [92] 2.10, 2.90 Ogungbe et al [48] triosephosphate isomerase 2VXN, [93] 2Y61 [94] 0.82, 0.99 Ogungbe et al [48] L. panamensis leishmanolysin -GP63 homologue model -Mercado-Camargo, et al [95] Using Molecular Operating Environment (MOE) software, [38] 241 molecular descriptors were calculated using the lowestenergy conformer of each compound, and a partial-least squares (PLS) analysis was performed. A low correlation value for L. donovani was obtained.…”

“…Biflavonoids from the Lanariaceae and Podocarpaceae were the best-docked molecules in this study. [95]…”

Use of Natural Products in Leishmaniasis Chemotherapy: An Overview

“…These four flavonoids demonstrated the same pattern of interactions for both Leishmania species. Lanaroflavone was the most promising compound of all considering binding affinity (Mercado-Camargo et al, 2020).…”