Identification of novel inhibitors of high affinity iron permease (FTR1) through implementing pharmacokinetics index to fight against black fungus: An in silico approach.

ABSTRACT

Mucormycosis is a life-threatening fungal infection, particularly in immunocompromised patients. Mucormycosis has been reported to show resistance to available antifungal drugs and was recently found in COVID-19 as a co-morbidity that demands new classes of drugs. In an attempt to find novel inhibitors against the high-affinity iron permease (FTR1), a novel target having fundamental importance on the pathogenesis of mucormycosis, 11,000 natural compounds were investigated in this study. Virtual screening and molecular docking identified two potent natural compounds [6',7,7,10',10',13'-hexamethylspiro[1,8-dihydropyrano[2,3-g]indole-3,11'-3,13-diazatetracyclo[5.5.2.01,9.03,7]tetradecane]-2,9,14'-trione and 5,7-dihydroxy-3-(2,2,8,8-tetramethylpyrano[2,3-f]chromen-6-yl)chromen-4-one] that effectively bind to the active cavity of FTR1 with a binding affinity of -9.9 kcal/mol. Multiple non-covalent interactions between the compounds and the active residues of this cavity were noticed, which is required for FTR1 inhibition. These compounds were found to have inhibitory nature and meet essential requirements to be drug-like compounds with a considerable absorption, distribution, metabolism, and excretion (ADME) profile with no toxicity probabilities. Molecular dynamics simulation confirms the structural compactness and less conformational variation of the drug-protein complexes maintaining structural stability and rigidity. MM-PBSA and post-simulation analysis predict binding stability of these compounds in the active cavity. This study hypothesizing that these compounds could be a potential inhibitor of FTR1 and will broaden the clinical prospects of mucormycosis.