Molecular Docking and Dynamics Simulation Revealed Ivermectin as Potential Drug against Schistosoma-Associated Bladder Cancer Targeting Protein Signaling: Computational Drug Repositioning Approach.

Arif Jamal Siddiqui,Kundan Kumar Chaubey,Manojkumar Sachidanandan,Mohammad Faheem Khan,Arshad Jamal,Pankaj Sharma,Mohd Adnan,Sadaf Jahan,Walid Sabri Hamadou,Manish Goyal,Syed Amir Ashraf,Riadh Badraoui,Mejdi Snoussi

doi:10.3390/medicina57101058

Abstract

Urogenital schistosomiasis is caused by Schistosoma haematobium (S. haematobium) infection, which has been linked to the development of bladder cancer. In this study, three repurposing drugs, ivermectin, arteether and praziquantel, were screened to find the potent drug-repurposing candidate against the Schistosoma-associated bladder cancer (SABC) in humans by using computational methods. The biology of most glutathione S-transferases (GSTs) proteins and vascular endothelial growth factor (VEGF) is complex and multifaceted, according to recent evidence, and these proteins actively participate in many tumorigenic processes such as cell proliferation, cell survival and drug resistance. The VEGF and GSTs are now widely acknowledged as an important target for antitumor therapy. Thus, in this present study, ivermectin displayed promising inhibition of bladder cancer cells via targeting VEGF and GSTs signaling. Moreover, molecular docking and molecular dynamics (MD) simulation analysis revealed that ivermectin efficiently targeted the binding pockets of VEGF receptor proteins and possessed stable dynamics behavior at binding sites. Therefore, we proposed here that these compounds must be tested experimentally against VEGF and GST signaling in order to control SABC. Our study lies within the idea of discovering repurposing drugs as inhibitors against the different types of human cancers by targeting essential pathways in order to accelerate the drug development cycle.

Highlights

Despite the in advancements of prognosis therapies, bladder cancer is the eleventh most leading urological cancer that is continuously contributing a 3.0% burden to total cancer with an estimated 573,278 new cases and 212,536 deaths worldwide as obtained from the GLOBOCAN database 2020 [1]
S. haematobium, a parasitic flatworm that infects more than 100 million people mostly in the developing world, is the causative agent of urogenital schistosomiasis, and it is associated with a high incidence of squamous cell carcinoma of the bladder [6]
In this study, we evaluated the efficacy of ivermectin and arteether in the bladder cancer caused by S. haematobium following a repurposing approach analyzing by molecular docking and Molecular Dynamics (MD) simulations

Summary

Introduction

Despite the in advancements of prognosis therapies, bladder cancer is the eleventh most leading urological cancer that is continuously contributing a 3.0% burden to total cancer with an estimated 573,278 new cases and 212,536 deaths worldwide as obtained from the GLOBOCAN database 2020 [1]. Apart from chemical agents, biological factors such as bacterial infections and other parasites play a key role in predisposing individuals to bladder cancer [5]. S. haematobium is released from infected freshwater snails via chronic granulomatous inflammation in the mucosal and submucosal linings of the urinary bladder. This cascade results in squamous cell carcinoma which is more prevalent and recurrent than compared to conventional transitional cell carcinoma of the urinary bladder [7]. A growing amount of evidence points to angiogenesis playing a key role in SABC as well as in schistosomiasis This statement may seem to be a paradox, since schistosomes are intravascular parasites that cause damage by destroying the blood vessels. Angiogenesis, or the formation of new endothelial sprouts from pre-existing postcapillary venules, is a well-known characteristic of inflammatory diseases, wound repair and provides support for tumor progression [6,8]

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