FBDD: In-silico STRATEGY TO INHIBIT MPRO ACTIVITY USING DRUGS FROM PREVIOUS OUTBREAKS

Gauravi N  Trivedi; Janhavi T  Karlekar; Khushbu  Dhimmar; Hetalkumar  Panchal

doi:10.18006/2021.9(4).472.480

Authors

Gauravi N Trivedi Post Graduate Department of Biosciences, Centre of Advanced Study in Bioresource Technology Sardar Patel University, Satellite campus, Bakrol-Vadtal road, Bakrol - 388315, Anand, Gujarat, India.
Janhavi T Karlekar Indukaka Ipcowala Centre for Interdisciplinary Studies in Science and Technology Sardar Patel University, Nr. Bus Stop, B/h Shastri Maidan, Vallabh Vidyanagar – 388120, Gujarat, India.
Khushbu Dhimmar Post Graduate Department of Biosciences, Centre of Advanced Study in Bioresource Technology Sardar Patel University, Satellite campus, Bakrol-Vadtal road, Bakrol - 388315, Anand, Gujarat, India.
Hetalkumar Panchal Post Graduate Department of Biosciences, Centre of Advanced Study in Bioresource Technology Sardar Patel University, Satellite campus, Bakrol-Vadtal road, Bakrol - 388315, Anand, Gujarat, India.

DOI:

https://doi.org/10.18006/2021.9(4).472.480

Keywords:

Main protease, Mpro, FBDD, Binding Affinity, Lead-like

Abstract

Main protease (M^pro) and Spike (S) proteins are said potential drug targets of COVID-19. Pneumonia like respiratory illness caused by SARS-CoV-2 is spreading rapidly due to its replication and transmission rate. Protease is the protein that is involved in both replication and transcription. Since CoV-2 shares, genomic similarity with CoV and MERS-CoV, drugs from previous outbreaks are used as primary treatment of the disease. In-silico drug development strategies are said to be faster and effective than in-vitro with a lesser amount of risk factors. Fragment Based Drug Designing (FBDD), also known as rational drug design in which a potential target protein is selected and docked with a lead-like molecule that eventually leads to drug development. Nine (9) drugs that are currently being used to treat patients of coronavirus were selected in this study from the latest literature review and fragmented as per rules followed by crosslinking of drug fragments using editor tools. These native drugs and synthesized drugs were then docked against the main protease. Results of the study revealed that one of the crosslinked lead-like compounds showed a higher binding affinity (∆G) more than any of the native compounds. Further, the results of this study suggested that the combination of potential drugs can be an effective way to develop new drugs to treat a deadly disease.

References

Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R (2003) Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. Science 300(5626): 1763-1767.

Antoine D, Olivier M and Vincent Z (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports 7(1): 42717.

Aparoy P, Reddy KK, Reddanna P (2012) Structure and ligand based drug design strategies in the development of novel 5- LOX inhibitors. Current Medicinal Chemistry 19(22):3763-78.

Bienstock RJ (2011) Overview: Fragment-Based Drug Design. Library Design, Search Methods, and Applications of Fragment-Based Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, Chapter 1, Pp 1-26.

Gimeno A, Mestres-Truyol J, Ojeda-Montes MJ, Macip G, Saldivar-Espinoza B, Cereto-Massagué A, Pujadas G, Garcia-Vallvé S (2020) Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition. International Journal of Molecular Sciences 21(11): 3793.

Hilgenfeld R, Anand K, Mesters JR, Rao Z, Shen X, Jiang H, Tan J, Verschueren KH (2006) Structure and dynamics of SARS coronavirus main proteinase (Mpro). Advances in Experimental Medicine and Biology 91: 581-585.

Honegger A (2017) Introduction to PyMOL DOI: 10.13140/RG.2.2.19625.80483.

Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, Ippolito G, Mchugh TD, Memish ZA, Drosten C, Zumla A, Petersen E (2020) The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China. International Journal of Infectious Diseases 91: 264-266.

Ihlenfeldt W (2008) A virtual file system for the PubChem chemical structure and bioassay database. Chemistry Central Journal 2: 26.

Jonkers T (2015) Selective Optimization of Side Activities (SOSA) in Drug Discovery. The Practice of Medicinal Chemistry: Fourth Edition, Turnhoutseweg, Beerse, Belgium.

Kirsch P, Hartman AM, Hirsch AKH, Empting M (2019) Concepts and Core Principles of Fragment-Based Drug Design. Molecules 24(23): 4309.

Langer T, Wermuth CG (2012) Selective Optimization of Side Activities (SOSA): A Promising way for Drug Discovery. Polypharmacology in Drug Discovery: First Edition, Wiley Online Library, Ch 11, 227-243.

Li G, De Clercq E (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 19: 19-20.

Liu Y, Gayle AA, Wilder-Smith A, Rocklöv J (2020) The reproductive number of COVID-19 is higher compared to SARS coronavirus. Journal of travel medicine 27:1-4.

Panda PK, Arul MN, Patel P, Verma SK, Luo W, Rubahn HG, Mishra YK, Suar M, Ahuja R (2020) Structure-based drug designing and immunoinformatics approach for SARS-CoV-2. Science Advances 6:1-38.

Park H, Lee J, Lee S (2006) Critical Assessment of the Automated AutoDock as a New Docking Tool for Virtual Screening. PROTEINS: Structure, Function, and Bioinformatics 65:549–554.

Rani R, Singh A, Pareek A, Tomar S (2020) In silico Guided Drug Repurposing to Combat SARS-CoV-2 by Targeting Mpro, the key virus specific protease. ChemRxiv 10.26434/chemrxiv.12030345.v1.

Sliwoski G, Kothiwale S, Meiler J, Lowe EW Jr. (2014) Computational methods in drug discovery. Beilstein Journal of Organic Chemistry 12: 2694-2718.

Snijder EJ, van der Meer Y, Zevenhoven-Dobbe J, Onderwater JJ, van der Meulen J, Koerten HK, Mommaas AM (2006) Ultrastructure and Origin of Membrane Vesicles Associated with the Severe Acute Respiratory Syndrome Coronavirus Replication Complex. Journal of Virology 80: 5927-5940.

Trott O, Olson AJ (2009) AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry 31(2):455-61.

Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a

program to generate schematic diagrams of protein-ligand interactions Clean up structure. Protein Engineering 8: 127-134.

Wermuth CG (2004) Selective Optimization of Side Activities: Another Way for Drug Discovery. Journal of Medicinal Chemistry 47(6):1303-14.

Yang H, Bartlam M, Rao Z (2006) Drug Design Targeting the Main Protease, the Achilles' Heel of Coronaviruses. Current Pharmaceutical Design 12(35): 4573-90.