Preprint / Version 1

Inferring Therapeutic Targets in Candida albicans and Possible Inhibition through Natural Products: A Binding and Physiological Based Pharmacokinetics Snapshot

Authors

  • Zarrin Basharat Jamil–ur–Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • Kanwal Khan Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • Khurshid Jalal HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • Sulaiman Alnasser Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia
  • Sania Majeed Jamil–ur–Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
  • Marium Zehra Jamil–ur–Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

Keywords:

Candida albicans, fructose-bisphosphate aldolase, CADD, dynamics simulation, pharmacokinetics, ADMET

Abstract

Despite being responsible for invasive infections, fungal pathogens have been underrepresented in computer aided therapeutic target mining and drug design. Excess of Candida albicans causes candidiasis, causative of thrush and vaginal infection due to off-balance. In this study, we attempted to mine drug targets (n = 46) using a subtractive proteomic approach in this pathogenic yeast and screen natural products with inhibition potential against fructose-bisphosphate aldolase (FBA) of the C. albicans. The top compound selected on the basis of best docking score from traditional Indian medicine/Ayurvedic library was (4-Hydroxybenzyl)thiocarbamic acid, from the ZINC FBA inhibitor library was ZINC13507461 (IUPAC name: [(2R)-2-hydroxy-3-phosphonooxypropyl] (9E,12E)-octadeca-9,12-dienoate), and from traditional Tibetan medicine/Sowa rigpa was Chelerythrine (IUPAC name: 1,2-Dimethoxy-12-methyl-9H-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium), compared to the control (2E)-1-(4-nitrophenyl)-2-[(4-nitrophenyl)methylidene]hydrazine. No Ames toxicity was predicted for prioritized compounds while control depicted this toxicity. (4-Hydroxybenzyl)thiocarbamic acid showed hepatotoxicity, while Chelerythrine depicted hERG inhibition, which can lead to QT syndrome, so we recommend ZINC13507461 for further testing in lab. Pharmacological based pharmacokinetic modeling revealed that it has low bioavailability and hence, absorption in healthy state. In cirrhosis and renal impairment, absorption and plasma accumulation increased so we recommend further investigation into this occurrence and recommend high dosage in further tests to increase bioavailability. Keywords: Candida albicans, fructose-bisphosphate aldolase, CADD, dynamics simulation, pharmacokinetics, ADMET

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