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Indian Journal of Pharmaceutical Education and ResearchNOW IN
Article

Targeting Alpha-Amylase: Discovering Novel Inhibitors through E-Pharmacophore Modeling and in vitro studies

Norah Saeed Al-Zahrani1, Basiouny El-Gamal1,2, Mohamed Abd Ellatif1,3★, Mohamed Babiker Abd Elrouf1, Alam Eldin Musa Mustafa Musa4,5, Niemat Mohammed Tahir Ali4, Marya Ahsan6, Ayaz Khurram Mallick1, Ayyub Ali Patel1, Safaa Omer1, Muniera Mohieldeen1, Hagar Mohamed Mohamed7,8, Marwa Saeed1, Safa Mousa Al-Haider4, Mohammed Abdullah Alshehri4★ Corresponding author

  1. 1Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.
  2. 2Healthcare and Pharma Department, Planaletix, Dubai, UNITED ARAB EMIRATES.
  3. 3Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, EGYPT.
  4. 4Department of Child Health, King Khalid University, Abha, SAUDI ARABIA.
  5. 5Department of Pediatrics, University of Kordofan, Al-Ubayyid, SUDAN.
  6. 6Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, SAUDI ARABIA.
  7. 7Department of Medical Laboratory Analysis, Faculty of Medical and Health Sciences, Liwa University, Abu Dhabi, UNITED ARAB EMIRATES.
  8. 8Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, EGYPT.

CORRESPONDENCE

Mohamed Abd Ellatif

Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, SAUDI ARABIA.

mabdellatif@kku.edu.sa

Received: 18-04-2025; Revised: 09-06-2025; Accepted: 28-08-2025.

Volume 60, Issue 1 · pp. 383–392 · PUBLISHED 2018 · DOI: 10.5530/ijper.20261204

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ABSTRACT

Background: Diabetes mellitus is a metabolic disorder affecting millions worldwide, with prevalence continuing to rise globally. A major therapeutic challenge is controlling postprandial blood glucose spikes that contribute to chronic hyperglycemia and associated vascular complications in diabetes. Pancreatic alpha-amylase is a key enzyme responsible for digesting dietary carbohydrates into absorbable sugars, making it an attractive target for managing postprandial hyperglycemia. While inhibitors like acarbose are available, side effects limit their use. Structure-guided drug design can reveal improved candidates. Materials and Methods: The X-ray structure of acarbose-bound alpha-amylase guided pharmacophore modeling to encode critical chemical features for inhibition. Database screening retrieved compounds matching this bioactive geometry. Top hits through pharmacophore modeling were evaluated through molecular docking versus co-crystallized references. Results: A validated 7-feature pharmacophore model captured essential hydrogen bonding and shape complementarity constraints within the enzyme active site. Screening retrieved distinct chemotypes scored well on pharmacophoric fit and strain energy. Molecular docking confirmed the top hit CID70684192 having strong predicted affinity (binding energy -7.1 kcal/mol) through conserved polar contacts and shape complementarity. In in vitro studies, CID: 70684192 showed no significant effect on the viability of AR4-2J pancreatic cells at various concentrations and exposure times. However, treatment of rat AR42J pancreatic cells with IC50 concentration CID: 70684192 (7 nM) significantly decreased alpha-amylase activity in treated cells compared to control. Conclusion: An integrated in silico and in vitro approach discovered novel alpha-amylase inhibitors with robust computational evidence of improved predicted activity over existing drugs. These represent promising candidates for experimental testing to reveal better tolerated therapies aiding diabetes management and postprandial glucose control. Structure-guided design enabled rapid identification of bioactive small molecules from chemical space.

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    Al-Zahrani, N. S., El-Gamal, B., Ellatif, M. A., Elrouf, M. B. A., Musa, A. E. M. M., Ali, N. M. T., Ahsan, M., Mallick, A. K., Patel, A. A., Omer, S., Mohieldeen, M., Mohamed, H. M., Saeed, M., Al-Haider, S. M., & Alshehri, M. A. (2018). Targeting Alpha-Amylase: Discovering Novel Inhibitors through E-Pharmacophore Modeling and in vitro studies. Indian Journal of Pharmaceutical Education and Research, 60(1), 383–392. https://doi.org/10.5530/ijper.20261204