June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Artificial intelligence and experimental studies to understand the transporters role in ocular toxicity of systemic drugs
Author Affiliations & Notes
  • Manisha Malani
    Pharmacy, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Surbhi Sharma
    Computer Science, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Manisha Jhunjhunwala
    Computer Science, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Manthan S Hiremath
    Pharmacy, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Shovan Lal Gayen
    Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India
  • Chittaranjan Hota
    Computer Science, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Jayabalan Nirmal
    Pharmacy, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, India
  • Footnotes
    Commercial Relationships   Manisha Malani None; Surbhi Sharma None; Manisha Jhunjhunwala None; Manthan Hiremath None; Shovan Gayen None; Chittaranjan Hota None; Jayabalan Nirmal None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 689 – F0143. doi:
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      Manisha Malani, Surbhi Sharma, Manisha Jhunjhunwala, Manthan S Hiremath, Shovan Lal Gayen, Chittaranjan Hota, Jayabalan Nirmal; Artificial intelligence and experimental studies to understand the transporters role in ocular toxicity of systemic drugs. Invest. Ophthalmol. Vis. Sci. 2022;63(7):689 – F0143.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Despite the ocular barriers, systemic drugs enter eye and causes toxicity. We hypothesize membrane transporters expressed in lacrimal gland (LG) to transport endogenous molecules from blood to tear, could falsely recognize the systemic drugs thereby gives access to eye. Hence, to understand the role of transporters (Organic Cation Transporter-1(OCT1)) in ocular toxicity, Artificial Intelligence (AI) methods and molecular docking studies were used to screen the drugs. Expression of OCT1 in LG and invivo tear kinetics study of predicted substrate (Cyclophosphamide(Cyc)) for OCT1 was performed to delineate the functional role of OCT1 in LG.

Methods : AI models were developed using a dataset of 193 drugs (substrate/non-substrates for OCT1) to predict drug-OCT1 interaction. Molecular Mechanics/Generalized Born Surface Area (MMGBSA) was used to calculate binding energy of protein (homology model of OCT1) and ligand (substrate/non-substrate/toxic drugs). Around 513 toxic drugs were screened through AI models and their binding energies were calculated using MMGBSA to classify them as substrate or non-substrate for OCT1. Expression of OCT1 in rabbit’s LG was confirmed by real time polymerase chain reaction. Invivo tear kinetics was performed to validate AI predictions and the functional role of OCT1 in LG. Cyc was injected intravenously to rabbits (n=4) with or without topical OCT1 inhibitor (Atropine). Tear was collected using Schirmer strips at various time points and analyzed using HPLC. Data was presented as mean ± SD and analyzed using t-test. P<0.05 was considered to be significant.

Results : Developed AI models showed an accuracy of 81% to 83%. Binding energy of substrate molecules was found to be below -14613.30 kcal/mol. Many novel interactions were unrevealed between drugs and OCT1 (Table1). RNA expression confirms the OCT1 presence in LG. Tear secretion of Cyc was decreased with inhibitor, with a significant difference at 1h (870 ± 60 ng/ml without inhibitor, 570 ± 60 ng/ml with inhibitor), p<0.01.

Conclusions : Out of 513 systemic drugs causing ocular toxicity, 44% of them were predicted as OCT1 substrate. OCT1 expression in LG, molecular docking and tear kinetics studies confirms the functional role of OCT1 in the entry of systemic drugs (OCT1 substrates) into eye. Further studies will be carried in detail to delineate the role of OCT1 in LG.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Predicted substrates of OCT1

Predicted substrates of OCT1

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