Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

3D QSAR Based Virtual Screening of Pyrido[1,2-a] Benzimidazoles as Potent Antimalarial Agents

Author(s): Kalicharan Sharma, Apeksha Srivastava, Pooja Tiwari, Shweta Sharma, Mohammad Shaquiquzzaman, M. Mumtaz Alam and Mymoona Akhter*

Volume 16, Issue 3, 2019

Page: [301 - 312] Pages: 12

DOI: 10.2174/1570180815666180502115147

Price: $65

Abstract

Background: Development of novel antimalarial agents has been one of the sought areas in medicinal chemistry. In this study the same was done by virtual screening of in-house database on developed QSAR model.

Methods: A six point pharmacophore model was generated (AADHRR.56) from 41 compounds using PHASE module of Schrodinger software and used for pharmacophore based search. Docking studies of the obtained hits were performed using GLIDE. Most promising hit was synthesized & biologically evaluated for antimalarial activity.

Result: The best generated model was found to be statistically significant as it had a high correlation coefficient r2= 0.989 and q2 =0.76 at 3 component PLS factor. The significance of hypothesis was also confirmed by high Fisher ratio (F = 675.1) and RMSE of 0.2745. The model developed had good predicted coefficient (Pearson R = 0.8826). The virtual screening on this model resulted in six hits, which were docked against FP-2 enzyme. The synthesized compound displayed IC50 value of 0.27µg/ml against CQS (3D7) and 0.57μg/ml against CQR (RKL9).

Conclusion: 3D QSAR studies reviled that hydrophobic groups are important for anti-malarial activity while H-donor is less desirable for the same. Electron withdrawing groups at R1 position favours the activity. The biological activity data of the synthesized hit proved that the pharmacophore hypothesis developed could be utilized for developing novel anti-malarial drugs.

Keywords: Benzimidazoles, antimalarial, pharmacophore, 3D Quantitative Structure Activity Relationship (3D-QSAR), schrodinger software, virtual screening.

« Previous Next »
Graphical Abstract

[1]
Breman, J.G.; Egan, A.; Keusch, G.T. The intolerable burden of malaria: A new look at the numbers. Am. J. Trop. Med. Hyg., 2001, 64, 4-7.
[2]
Na-Bangchang, K.; Congpuong, K. Current malaria status and distribution of drug resistance in East and Southeast Asia with special focus to Thailand. Tohoku J. Exp. Med., 2007, 211, 99-113.
[3]
Wernsdorfer, W.H. Epidemiology of drug resistance in malaria. Acta Trop., 1994, 56, 143.
[4]
Sijwali, P.S.; Rosenthal, P.J. Gene disruption confirms a critical role for the cysteine protease falcipain-2 in haemoglobin hydrolysis by Plasmodium falciparum. Proc. Nat. Acad. Sci. USA, 2004, 101, 4384-4389.
[5]
Sijwali, P.S.; Shenai, B.R.; Gut, J.; Singh, A.; Rosenthal, P.J. Expression and characterization of the Plasmodium falciparum hemoglobinase falcipain-3. Biochem. J., 2001, 360, 481-489.
[6]
Shenai, B.R.; Sijwali, P.S.; Singh, A.; Rosenthal, P.J. Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum. J. Biol. Chem., 2000, 2759, 29000-29010.
[7]
Ndakala, A.J.; Gessner, R.K.; Gitari, P.W.; October, N.K.; White, L.; Hudson, A.; Fakorede, F.D.; Shackleford, M.; Kaiser, M.; Yeates, C.; Charman, S.A.; Chibale, K. Antimalarial pyrido[1,2-a] benzimidazole. J. Med. Chem., 2011, 54, 4581-4589.
[8]
Kerr, I.D.; Lee, J.H.; Pandey, K.C.; Harrison, A.; Sajid, M.; Rosenthal, P.J.; Brinen, L.S. Structure of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity. J. Med. Chem., 2009, 52, 852-857.
[9]
Rosenthal, P.J.; McKerrow, J.H.; Aikawa, M.; Nagasawa, H.; Leech, J.H. A malaria cysteine proteinase is necessary for haemoglobin degradation by Plasmodium falciparum. J. Clin. Invest., 1988, 82, 1560-1566.
[10]
Palmer, J.T.; Rasnick, D.; Klaus, J.L.; Brömme, D. Vinylsulfones as mechanism-based cysteine protease inhibitors. J. Med. Chem., 1995, 38, 3193-3196.
[11]
Schlitzer, M. Antimalarial drugs-what is in use and what is in pipeline. Arch. Pharm. , 2008, 341, 149-163.
[12]
Rosenthal, P.J.; Olson, J.E.; Lee, G.K.; Palmer, J.T.; Klaus, J.L.; Rasnickm, D. Antimalarial effects of vinyl sulfone cysteine protease inhibitors. Antimicro. Agents Chemother., 1996, 40, 1600-1603.
[13]
Lill, M.A. Multi-dimensional QSAR in drug discovery. Drug Discov. Today, 2007, 12, 1013-1017.
[14]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110, 5959-5967.
[15]
Phase version 9.4, Schrodinger, LLC, New York, USA 2009.
[16]
Canvas version 9.4, Schrodinger, LLC, New York, USA 2009.
[17]
The Advantages of Accurate 3D Ligand Libraries LigPrep, Schrödinger, LLC, New York, NY 2018.https://www.schrodinger. com/ligprep
[18]
Marijana, H.; Gordana, P.; Marko, M.; Marijeta, K.; Grace, K-Z. Eur. J. Med. Chem., 2010, 45, 2405-2417.
[19]
Bohets, H.; Annaert, P.; Mannens, G.; Van, B.L.; Anciaux, K.; Verboven, P.; Meuldermans, W.; Lavrijsen, K. Curr. Top. Med. Chem., 2001, 1, 367-383.

Rights & Permissions Print Cite
Article Metrics
21
4
© 2024 Bentham Science Publishers | Privacy Policy