pp 1-18 | Cite as
Development of a Web-Server for Identification of Common Lead Molecules for Multiple Protein Targets
Due to increasing unresponsiveness of drugs to single targets in the form of resistance or presence of alternate mechanisms in case of complex diseases and disorders, etc., the focus is shifting towards polypharmacology. It is desirable that a drug works on multiple targets to elicit guaranteed/multiplier effect. Here, we provide a one stop solution to the quest of finding common leads for multiple protein targets. The computational protocol designed involves screening, docking, and scaffold-based optimization of hit molecules from a variety of compound libraries against any two specified protein targets. The protocol is validated with five case studies involving five pairs of proteins with varying active site similarities. The methodology is able to recover the known common FDA approved drugs against them. A web-server named “Multi-Target Ligand Design” is created and made freely accessible at http://www.scfbio-iitd.res.in/multitarget/.
KeywordsMulti-target drug design Polypharmacology Scaffold-based optimization Screening and docking Structure based ligand design
Funding from the Department of Biotechnology, Govt. of India, to SCFBio is gratefully acknowledged. A.J. and A.P. are Institute Fellows. R.B. is a DST INSPIRE Fellow.
Author contributions: B.J. conceived the project. A.J., R.B., A.P. carried out the computational development. All authors analyzed the results and wrote the manuscript. M.S. helped in web enabling of the server. All authors have given approval to the final version of the manuscript.
- 14.Boran ADW, Iyengar R (2010) Systems approaches to polypharmacology and drug discovery. Curr Opin Drug Discov Devel 13:297–309. https://doi.org/10.1126/scisignal.2001965.IntroductionCrossRefGoogle Scholar
- 20.Goldner T, Hewlett G, Ettischer N et al (2011) The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol 85:10884–10893. https://doi.org/10.1128/JVI.05265-11CrossRefGoogle Scholar
- 30.Gupta SC, Kim JH, Prasad S, Aggarwal BB (2010) Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 29:405–434. https://doi.org/10.1007/s10555-010-9235-2CrossRefGoogle Scholar
- 35.Holdeman R, Nehrt S, Strome S (1998) MES-2, a maternal protein essential for viability of the germline in Caenorhabditis elegans, is homologous to a Drosophila Polycomb group protein. Development 125:2457–2467Google Scholar
- 39.Ploemen JHTM, Johnson WW, Jespersen S et al (1994) Active-site tyrosyl residues are targets in the irreversible inhibition of a class Mu glutathione transferase by 2-(S-glutathionyl)-3,5,6-trichloro-1,4-benzoquinone. J Biol Chem 269:26890–26897Google Scholar
- 40.Ramsay RR, Majekova M, Medina M, Valoti M (2016) Key targets for multi-target ligands designed to combat neurodegeneration. Front Neurosci 10. https://doi.org/10.3389/fnins.2016.00375
- 55.NCI Database Download Page. http://cactus.nci.nih.gov/ncidb2/download.html
- 63.Nagarajan D, Chandra N (2013) PocketMatch (version 2.0): a parallel algorithm for the detection of structural similarities between protein ligand binding-sites. In: 2013 national conference on parallel computing technologies (PARCOMPTECH). IEEE, pp 1–6. https://doi.org/10.1109/ParCompTech.2013.6621397
- 64.Sim L, Jayakanthan K, Mohan S et al (2010) New glucosidase inhibitors from an ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata. Biochemistry 49:443–451. https://doi.org/10.1021/bi9016457CrossRefGoogle Scholar
- 65.Roig-Zamboni V, Cobucci-Ponzano B, Iacono R et al (2017) Structure of human lysosomal acid α-glucosidase—a guide for the treatment of Pompe disease. Nat Commun 8. https://doi.org/10.1038/s41467-017-01263-3
- 69.Cui JJ, Tran-Dubé M, Shen H et al (2011) Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 54:6342–6363. https://doi.org/10.1021/jm2007613CrossRefGoogle Scholar