Sławomir Filipek - Academia.edu (original) (raw)
Papers by Sławomir Filipek
MRS Proceedings, 2015
ABSTRACT Using all-atom molecular dynamics simulations in water environment, it was possible to d... more ABSTRACT Using all-atom molecular dynamics simulations in water environment, it was possible to demonstrate spontaneous and tight encapsulation of glucose oxidase (GOx) dimer by graphene 7 nm x 7 nm sheets linked together by linkers of different width and forming a flower-like or cross-like shapes. The partially overlapping graphene sheets compacted the structure of GOx dimer, bringing the monomers much closer to one another. We found that the most complete wrapping of the enzyme was achieved for the cross-like graphene. Encapsulation can be a useful way to obtain a large contact surface. However, an exceptionally tight binding by the graphene can also influence the positions of amino acids in the enzyme binding site resulting in less efficient catalytic reaction. Furthermore, such extensive encapsulation could block the access of the substrate to the active site of the enzyme. Contrary, a partial encapsulation by graphene using nano-sheets caused only small distortions of GOx structure while the contact surface with graphene was high.
Structure (London, England : 1993), Jan 3, 2016
Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered ... more Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered the first detailed structural insights for a mammalian pentameric ligand-gated ion channel. Based on this structure, we here performed a total of 2.8-μs all-atom molecular dynamics simulations to unravel at atomic detail how neurotransmitter binding on the extracellular domain induces sequential conformational transitions in the receptor, opening an ion channel and translating a chemical signal into electrical impulses across the membrane. We found that serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway. The structural transitions in the receptor's transmembrane part finally couple to the intrace...
Journal of Chemical Information and Modeling, 2016
The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened rece... more The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened receptor SMO targets, exposed the strengths and weaknesses of the currently used computational approaches. The test cases of 5-HT1B and 5-HT2B demonstrated that both the receptor structure and the ligand binding mode can be predicted with the atomic-detail accuracy, as long as the target-template sequence similarity is relatively high. On the other hand, the observation of a low target-template sequence similarity, e.g., between SMO from the frizzled GPCR family and members of the rhodopsin family, hampers the GPCR structure prediction and ligand docking. Indeed, in GPCR Dock 2013, accurate prediction of the SMO target was still beyond the capabilities of most research groups. Another bottleneck in the current GPCR research, as demonstrated by the 5-HT2B target, is the reliable prediction of global conformational changes induced by activation of GPCRs. In this work, we report details of our protocol used during GPCR Dock 2013. Our structure prediction and ligand docking protocol was especially successful in the case of 5-HT1B and 5-HT2B-ergotamine complexes for which we provide one of the most accurate predictions. In addition to a description of the GPCR Dock 2013 results, we propose a novel hybrid computational methodology to improve GPCR structure and function prediction. This computational methodology employs two separate rankings for filtering GPCR models. The first ranking is ligand-based while the second is based on the scoring scheme of the recently published BCL method. In this work, we prove that the use of knowledge-based potentials implemented in BCL is an efficient way to cope with major bottlenecks in the GPCR structure prediction. Thereby, we also demonstrate that the knowledge-based potentials for membrane proteins were significantly improved, because of the recent surge in available experimental structures.
ChemMedChem, 2015
Alzheimer's disease (AD) is a maj... more Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.
Langmuir : the ACS journal of surfaces and colloids, Jan 29, 2015
Lyotropic liquid crystalline systems are excellent carriers for drugs due to their biocompatibili... more Lyotropic liquid crystalline systems are excellent carriers for drugs due to their biocompatibility, stability in aqueous environment and well-defined structure that allow to host significantly larger amounts of drugs than carriers such as liposomes or gold nanoparticles. Incorporating the drug within the mesophase gel, or the cubosome/hexosome nanoparticles decreased its toxic effects towards healthy cells, while appropriate mechanisms can stimulate the release of the drug from the carrier when it approaches the cancerous cell environment. Electrochemical methods - chronocoulometry and voltammetry at micro and normal size electrodes - are used for the first time to simultaneously determine the diffusion coefficients and effective concentrations of a toxic anticancer drug - doxorubicin - in the channels of three liquid-crystalline lipidic cubic phases. This approach was instrumental in demonstrating that the drug diffusion and kinetics of release from the mesophases depend on the aq...
Langmuir, 2015
Poly-l-glutamic acid (PLGA) forms amyloid-like β2-fibrils with the main spectral component of vib... more Poly-l-glutamic acid (PLGA) forms amyloid-like β2-fibrils with the main spectral component of vibrational amide I' band unusually shifted below 1600 cm(-1). This distinct infrared feature has been attributed to the presence of bifurcated hydrogen bonds coupling C═O and N-D (N-H) groups of the main chains to glutamate side chains. Here, we investigate how decreasing the chain length of PLGA affects its capacity to form β2-fibrils. A series of acidified aqueous solutions of synthetic (l-Glu)n peptides (n ≈ 200, 10, 6, 5, 4, and 3) were incubated at high temperature. We observed that n = 4 is the critical chain length for which formation of aggregates with the β2-like infrared features is still observed under such conditions. Interestingly, according to atomic force microscopy (AFM), the self-assembly of (l-Glu)n chains varying vastly in length produces fibrils with rather uniform diameters of approximately 4-6 nm. Kinetic experiments on (l-Glu)5 and (l-Glu)200 peptides indicate that the fibrillation is significantly accelerated not only in the presence of homologous seeds but also upon cross-seeding, suggesting thereby a common self-assembly theme for (l-Glu)n chains of various lengths. Our results are discussed in the context of mechanisms of amyloidogenic fibrillation of homopolypeptides.
Angewandte Chemie (International ed. in English), Jan 27, 2016
Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphos... more Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 R...
The Journal of Physical Chemistry C, Apr 22, 2009
... Jan S. Jaworski* , Agnieszka Kosson , Sławomir Filipek , Michał Koli ski and ... thre... more ... Jan S. Jaworski* , Agnieszka Kosson , Sławomir Filipek , Michał Koli ski and ... three simplest carbonyl derivatives of triptindane (C 3v -tribenzo[3.3.3]propellane, T), namely 9-triptindanone (T1), 9,10-triptindanedione (T2), and 9,10,11-triptindanetrione (T3) (Chart ), it was ...
Cell Biochem Biophys, 2006
Chemmedchem, Apr 14, 2008
J Coord Chem, 2000
... THE INFLUENCE OF STRUCTURAL EFFECTS ON THlE COMPLEXING ABILITY OF CROWN ETHERS SLAWOMIR FILIP... more ... THE INFLUENCE OF STRUCTURAL EFFECTS ON THlE COMPLEXING ABILITY OF CROWN ETHERS SLAWOMIR FILIPEK, PAWEL RUDZINSKI and MAREK K. KALINOWSKI* Department of Chemistry, University of Warsaw, 1 Pasteur St., 02-093 Warszawa, Poland ...
The Open Structural Biology Journal, 2008
MRS Proceedings, 2015
ABSTRACT Using all-atom molecular dynamics simulations in water environment, it was possible to d... more ABSTRACT Using all-atom molecular dynamics simulations in water environment, it was possible to demonstrate spontaneous and tight encapsulation of glucose oxidase (GOx) dimer by graphene 7 nm x 7 nm sheets linked together by linkers of different width and forming a flower-like or cross-like shapes. The partially overlapping graphene sheets compacted the structure of GOx dimer, bringing the monomers much closer to one another. We found that the most complete wrapping of the enzyme was achieved for the cross-like graphene. Encapsulation can be a useful way to obtain a large contact surface. However, an exceptionally tight binding by the graphene can also influence the positions of amino acids in the enzyme binding site resulting in less efficient catalytic reaction. Furthermore, such extensive encapsulation could block the access of the substrate to the active site of the enzyme. Contrary, a partial encapsulation by graphene using nano-sheets caused only small distortions of GOx structure while the contact surface with graphene was high.
Structure (London, England : 1993), Jan 3, 2016
Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered ... more Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered the first detailed structural insights for a mammalian pentameric ligand-gated ion channel. Based on this structure, we here performed a total of 2.8-μs all-atom molecular dynamics simulations to unravel at atomic detail how neurotransmitter binding on the extracellular domain induces sequential conformational transitions in the receptor, opening an ion channel and translating a chemical signal into electrical impulses across the membrane. We found that serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway. The structural transitions in the receptor's transmembrane part finally couple to the intrace...
Journal of Chemical Information and Modeling, 2016
The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened rece... more The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened receptor SMO targets, exposed the strengths and weaknesses of the currently used computational approaches. The test cases of 5-HT1B and 5-HT2B demonstrated that both the receptor structure and the ligand binding mode can be predicted with the atomic-detail accuracy, as long as the target-template sequence similarity is relatively high. On the other hand, the observation of a low target-template sequence similarity, e.g., between SMO from the frizzled GPCR family and members of the rhodopsin family, hampers the GPCR structure prediction and ligand docking. Indeed, in GPCR Dock 2013, accurate prediction of the SMO target was still beyond the capabilities of most research groups. Another bottleneck in the current GPCR research, as demonstrated by the 5-HT2B target, is the reliable prediction of global conformational changes induced by activation of GPCRs. In this work, we report details of our protocol used during GPCR Dock 2013. Our structure prediction and ligand docking protocol was especially successful in the case of 5-HT1B and 5-HT2B-ergotamine complexes for which we provide one of the most accurate predictions. In addition to a description of the GPCR Dock 2013 results, we propose a novel hybrid computational methodology to improve GPCR structure and function prediction. This computational methodology employs two separate rankings for filtering GPCR models. The first ranking is ligand-based while the second is based on the scoring scheme of the recently published BCL method. In this work, we prove that the use of knowledge-based potentials implemented in BCL is an efficient way to cope with major bottlenecks in the GPCR structure prediction. Thereby, we also demonstrate that the knowledge-based potentials for membrane proteins were significantly improved, because of the recent surge in available experimental structures.
ChemMedChem, 2015
Alzheimer's disease (AD) is a maj... more Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.
Langmuir : the ACS journal of surfaces and colloids, Jan 29, 2015
Lyotropic liquid crystalline systems are excellent carriers for drugs due to their biocompatibili... more Lyotropic liquid crystalline systems are excellent carriers for drugs due to their biocompatibility, stability in aqueous environment and well-defined structure that allow to host significantly larger amounts of drugs than carriers such as liposomes or gold nanoparticles. Incorporating the drug within the mesophase gel, or the cubosome/hexosome nanoparticles decreased its toxic effects towards healthy cells, while appropriate mechanisms can stimulate the release of the drug from the carrier when it approaches the cancerous cell environment. Electrochemical methods - chronocoulometry and voltammetry at micro and normal size electrodes - are used for the first time to simultaneously determine the diffusion coefficients and effective concentrations of a toxic anticancer drug - doxorubicin - in the channels of three liquid-crystalline lipidic cubic phases. This approach was instrumental in demonstrating that the drug diffusion and kinetics of release from the mesophases depend on the aq...
Langmuir, 2015
Poly-l-glutamic acid (PLGA) forms amyloid-like β2-fibrils with the main spectral component of vib... more Poly-l-glutamic acid (PLGA) forms amyloid-like β2-fibrils with the main spectral component of vibrational amide I' band unusually shifted below 1600 cm(-1). This distinct infrared feature has been attributed to the presence of bifurcated hydrogen bonds coupling C═O and N-D (N-H) groups of the main chains to glutamate side chains. Here, we investigate how decreasing the chain length of PLGA affects its capacity to form β2-fibrils. A series of acidified aqueous solutions of synthetic (l-Glu)n peptides (n ≈ 200, 10, 6, 5, 4, and 3) were incubated at high temperature. We observed that n = 4 is the critical chain length for which formation of aggregates with the β2-like infrared features is still observed under such conditions. Interestingly, according to atomic force microscopy (AFM), the self-assembly of (l-Glu)n chains varying vastly in length produces fibrils with rather uniform diameters of approximately 4-6 nm. Kinetic experiments on (l-Glu)5 and (l-Glu)200 peptides indicate that the fibrillation is significantly accelerated not only in the presence of homologous seeds but also upon cross-seeding, suggesting thereby a common self-assembly theme for (l-Glu)n chains of various lengths. Our results are discussed in the context of mechanisms of amyloidogenic fibrillation of homopolypeptides.
Angewandte Chemie (International ed. in English), Jan 27, 2016
Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphos... more Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1 R...
The Journal of Physical Chemistry C, Apr 22, 2009
... Jan S. Jaworski* , Agnieszka Kosson , Sławomir Filipek , Michał Koli ski and ... thre... more ... Jan S. Jaworski* , Agnieszka Kosson , Sławomir Filipek , Michał Koli ski and ... three simplest carbonyl derivatives of triptindane (C 3v -tribenzo[3.3.3]propellane, T), namely 9-triptindanone (T1), 9,10-triptindanedione (T2), and 9,10,11-triptindanetrione (T3) (Chart ), it was ...
Cell Biochem Biophys, 2006
Chemmedchem, Apr 14, 2008
J Coord Chem, 2000
... THE INFLUENCE OF STRUCTURAL EFFECTS ON THlE COMPLEXING ABILITY OF CROWN ETHERS SLAWOMIR FILIP... more ... THE INFLUENCE OF STRUCTURAL EFFECTS ON THlE COMPLEXING ABILITY OF CROWN ETHERS SLAWOMIR FILIPEK, PAWEL RUDZINSKI and MAREK K. KALINOWSKI* Department of Chemistry, University of Warsaw, 1 Pasteur St., 02-093 Warszawa, Poland ...
The Open Structural Biology Journal, 2008