Research objectives
The primary scientific objective of this project is to develop a protocol for the in silico design of inhibitors of Niemann-Pick type C1 protein (NPC1). The quintessence of this research is to create a virtual screening (VS) protocol that permits the prioritization of chemical compounds based on their potential inhibitory activity against NPC1 (a protein playing a crucial function in the process of Ebola virus infection). The application and improvement of the existing conceptual methodology targeting NPC1 inhibitors will allow broad exploration of the chemical space in search of new antiviral agents.
Methodology
The screening cascade will consist of several subsequent steps (prefiltering, pharmacophore mapping, docking protocol, ADMETox filter, clustering, visual inspection) to select the most valuable structures. Each stage of the cascade will be created using procedures developed at the Department of Medicinal Chemistry. In the planned tasks, the following methodologies will be upgraded and applied: descriptors calculations and analyses, pharmacophore modeling, homology modeling and docking protocols. The VS protocol will be used to evaluate a virtual combinatorial library of compounds (created within the project) and to select compounds for synthesis (in independent projects initiated in the Institute of Organic Chemistry and Analytical Chemistry in Orleans, France) of the most promising structures.
Research project impact
The realization of this project will create opportunities to establish structural requirements for compounds with potency to function as new antiviral agents that target one of the most dangerous viruses. The obtained VS protocol can be used multiple times both in commercial and virtual compound libraries. Moreover, this project will strengthen scientific cooperation between the Department of Medicinal Chemistry and the Institute of Organic Chemistry and Analytical Chemistry initiated several years ago. Positive results of this project may result in additional joint applications to extend the issues undertaken herein.
At least one scientific publication in a journal from the Master Journal List will be the notable effects of the research. It has to be stressed, however, that depending on how many different groups of NPC1 inhibitors will be further developed in Orleans more publications are highly probable. In addition, the results will be presented at both international and national conferences. The implementation of this program will also enhance the experience of the candidate in the management of independent scientific projects.
Principal Investigator
Dawid Warszycki, PhD
e-mail: warszyc@if-pan.krakow.pl
phone: +4812 66 23 301
More
Promotion:
a) publications:
1. Zahira Tber, Mylène Wartenberg, Jean-Eddy Jacques, Vincent Roy, Fabien Lecaille, Dawid Warszycki, Andrzej J. Bojarski, Gilles Lalmanach, Luigi A. Agrofoglio. Selective inhibition of human cathepsin S by 2,4,6-trisubstituted 1,3,5-triazine analogs. Bioorganic & Medicinal Chemistry, 2018, 26, 4310–4319.
2. Dawid Warszycki, Marek Śmieja, Rafal Kafel. Practical application of the Average Information Content Maximization (AIC-MAX) algorithm: selection of the most important structural features for serotonin receptor ligands. Molecular Diversity, 2017, 21, 2, 407-412.
b) participation in conferences:
1. Dawid Warszycki, Linn M. Evenseth, Andrzej J. Bojarski Lessons learned from docking with the presence of water molecules – does it worth it?, GPCR Workshop, December 5-9, 2017, Kailua-Kona, USA Abstract Poster
2. Dawid Warszycki, Vincent Roy, Luigi Agrofoglio, Andrzej J. Bojarski Development of the virtual screening cascade in search for inhibitors of Niemann-Pick C1 protein as a anti Ebola agents. 13th German Conference on Chemoinformatics, November 6-8, 2017, Mainz, Germany Abstract Poster
3. Dawid Warszycki, Vincent Roy, Luigi Agrofoglio, Andrzej J. Bojarski Application of the novel pharmacophore modelling methodology in search for Ebola virus inhibitors. III Sympozjum Chemii Medycznej, September 6-8, 2017, Wrocław, Poland