Exploration and identification of novel inhibitors against Knowpain-4 of P. knowlesi using a combinatorial 3D pharmacoph
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(2020) 9:67
ORIGINAL ARTICLE
Exploration and identification of novel inhibitors against Knowpain‑4 of P. knowlesi using a combinatorial 3D pharmacophore modeling approach Manoj Kumar Yadav1 · Ravi Rao Bharti2 · Mayank Rashmi3 Received: 26 May 2020 / Revised: 27 September 2020 / Accepted: 7 October 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract Papain-like cysteine protease of P. knowlesi is a significant target for the treatment of malaria infection. P. knowlesi poses a new threat to malaria eradication programs as it starts infecting humans. We have targeted P. knowlesi Knowpain-4 protein for inhibitor designing based on the molecular modeling simulations and structure-based pharmacophore modeling. In-depth sequence analysis reveals its crucial role in host hemoglobin degradation. Dihedral angles and QMEAN score analysis successfully validate the modeled structure of Knowpain4. The docking simulation leads to the prediction of E64 poses at the binding site of Knowpain4 protein. The ligand–receptor interaction information is used for generating five different pharmacophore models taking a diverse set of parameters. A combined 3D features-based, a pharmacophore model is assembled to screen in-house database. The presence of E64, along with 2,128 compounds in the output cross-confirms our screening model. Later on, top 22 screened compounds with higher relative pharmacophore score to E64 is selected for interaction study. The docking simulation experiments result in the identification of 6 compounds that occupies the functional, active site of Knowpain4 protein with high binding affinity. Further, pharmacokinetic studies showed that the identified compounds are potential bioactive molecules with unique scaffolds, and may have the potential to block the expression of Knowpain4 protease. Keywords Knowpain4 · Plasmodium · Merged feature-based pharmacophore modeling · Docking simulation · Pharmacokinetics Abbreviations ADMET Absorption, distribution, metabolism, excretion and toxicity KP4 Knowpain4 3D Three dimensional TPSA Topological Polar Surface Area HA Hydrogen bond acceptors HD Hydrogen bond donors BLAST Basic Local Alignment Search Tool * Manoj Kumar Yadav [email protected]; [email protected] 1
Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Sonepat, Haryana 131 029, India
2
Parasitology Laboratory, Department of Zoology, North-Eastern Hill University, Shillong, Meghalaya 793 022, India
3
Centre of Bioinformatics, IIDS, University of Allahabad, Prayagraj 211 002, India
CADD Computer aided drug design NCBI National Center for Biotechnology Information GUI Graphical user interface
1 Introduction Malaria is the most important tropical disease known to humankind. It remains a significant problem in tropical and subtropical regions of the world and exerts a heavy burden on the poorest and most vulnerable communities (Breman et al. 2004; Michael and Madon 2017). Within endemic countries, the low-income populatio
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