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Updated: Nov 8, 2025
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular
Mubarak A Alamri1, Muhammad Tahir Ul Qamar2, Obaid Afzal1
1Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Abstract:
Middle east respiratory syndrome coronavirus (MERS-CoV) is a fatal pathogen that poses a serious health risk worldwide and especially in the middle east countries. Targeting the MERS-CoV 3-chymotrypsin-like cysteine protease (3CLpro) with small covalent inhibitors is a significant approach to inhibit replication of the virus. The present work includes generating a pharmacophore model based on the X-ray crystal structures of MERS-CoV 3CLpro in complex with two covalently bound inhibitors. In silico screening of covalent chemical database having 31,642 compounds led to the identification of 378 compounds that fulfils the pharmacophore queries. Lipinski rules of five were then applied to select only compounds with the best physiochemical properties for orally bioavailable drugs. 260 compounds were obtained and subjected to covalent docking-based virtual screening to determine their binding energy scores. The top three candidate compounds, which were shown to adapt similar binding modes as the reported covalent ligands were selected. The mechanism and stability of binding of these compounds were confirmed by 100 ns molecular dynamic simulation followed by MM/PBSA binding free energy calculation. The identified compounds can facilitate the rational design of novel covalent inhibitors of MERS-CoV 3CLpro enzyme as anti-MERS CoV drugs.
Insights
Researchers identified potential new drugs targeting Middle East respiratory syndrome coronavirus (MERS-CoV). Computational methods screened compounds to find novel covalent inhibitors for the MERS-CoV 3CLpro enzyme, offering hope for new treatments.
Area of Science:
- * Medicinal Chemistry
- * Virology
- * Computational Biology
Background:
- * Middle East respiratory syndrome coronavirus (MERS-CoV) is a significant global health threat, particularly in the Middle East.
- * The MERS-CoV 3-chymotrypsin-like cysteine protease (3CLpro) is a key target for antiviral drug development.
- * Small covalent inhibitors offer a promising strategy to inhibit viral replication.
Purpose of the Study:
- * To generate a pharmacophore model for MERS-CoV 3CLpro.
- * To identify novel covalent inhibitors for MERS-CoV 3CLpro using in silico screening.
- * To validate the binding mechanism and stability of candidate inhibitors.
Main Methods:
- * Generation of a pharmacophore model based on MERS-CoV 3CLpro X-ray crystal structures.
- * In silico screening of a covalent chemical database (31,642 compounds).
- * Application of Lipinski's Rule of Five and covalent docking-based virtual screening.
- * Molecular dynamics simulations and MM/PBSA binding free energy calculations.
Main Results:
- * 378 compounds initially identified from virtual screening.
- * 260 compounds selected based on Lipinski's Rule of Five for oral bioavailability.
- * Top three candidate compounds exhibited similar binding modes to known covalent ligands.
- * Molecular dynamics and binding free energy calculations confirmed stability and mechanism of action.
Conclusions:
- * Identified three novel compounds with potential as covalent inhibitors of MERS-CoV 3CLpro.
- * These compounds can guide the rational design of new anti-MERS-CoV drugs.
- * The study provides a foundation for developing effective MERS-CoV therapeutics.
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