{"entity": "researcher", "timestamp": "2026-07-13T08:46:50.678Z", "family": "Poongavanam", "given": "Vasanthanathan", "initials": "V", "orcid": "0000-0002-8880-9247", "affiliations": ["Department of Chemistry-BMC, Uppsala University, 75123, Uppsala, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f"}}, "publications": [{"entity": "publication", "iuid": "d88276ac569d4cd0bd561502c908ae43", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d88276ac569d4cd0bd561502c908ae43.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d88276ac569d4cd0bd561502c908ae43"}}, "title": "Impact of Linker Composition on VHL PROTAC Cell Permeability.", "authors": [{"family": "Abeje", "given": "Yordanos Esubalew", "initials": "YE"}, {"family": "Wieske", "given": "Lianne H E", "initials": "LHE", "orcid": "0000-0003-4617-7605", "researcher": {"href": "https://publications.scilifelab.se/researcher/9ee9a8547a194235a4d32170996b53e9.json"}}, {"family": "Poongavanam", "given": "Vasanthanathan", "initials": "V", "orcid": "0000-0002-8880-9247", "researcher": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f.json"}}, {"family": "Maassen", "given": "Stefanie", "initials": "S"}, {"family": "Atilaw", "given": "Yoseph", "initials": "Y"}, {"family": "Cromm", "given": "Philipp", "initials": "P"}, {"family": "Lehmann", "given": "Lutz", "initials": "L"}, {"family": "Erdelyi", "given": "Mate", "initials": "M", "orcid": "0000-0003-0359-5970", "researcher": {"href": "https://publications.scilifelab.se/researcher/f772b571449e417ca6fda2eee361a0c3.json"}}, {"family": "Meibom", "given": "Daniel", "initials": "D", "orcid": "0000-0003-4978-9842", "researcher": {"href": "https://publications.scilifelab.se/researcher/3034131b5fc94a24b8ab1a350205d960.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}], "type": "journal article", "published": "2025-01-09", "journal": {"title": "J. Med. Chem.", "issn": "1520-4804", "volume": "68", "issue": "1", "pages": "638-657", "issn-l": "0022-2623"}, "abstract": "The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area. Our results suggest that the design of cell permeable VHL PROTACs could focus on linkers that facilitate shielding of polar surface area in the VHL ligand in a nonpolar but not in a polar environment. In addition, we found that not only intramolecular hydrogen bonds, but also NH-\u03c0 and \u03c0-\u03c0 interactions contribute to the stabilization of low-polarity conformations, and thereby to high cell permeability.", "doi": "10.1021/acs.jmedchem.4c02492", "pmid": "39693386", "labels": {"Swedish NMR Centre": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11726670"}], "notes": [], "created": "2025-11-27T08:14:24.112Z", "modified": "2025-11-27T08:14:24.481Z"}, {"entity": "publication", "iuid": "5f4b3a7c780f4555b649b7dc7c33670e", "links": {"self": {"href": "https://publications.scilifelab.se/publication/5f4b3a7c780f4555b649b7dc7c33670e.json"}, "display": {"href": "https://publications.scilifelab.se/publication/5f4b3a7c780f4555b649b7dc7c33670e"}}, "title": "Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies.", "authors": [{"family": "Begnini", "given": "Fabio", "initials": "F"}, {"family": "Poongavanam", "given": "Vasanthanathan", "initials": "V", "orcid": "0000-0002-8880-9247", "researcher": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f.json"}}, {"family": "Atilaw", "given": "Yoseph", "initials": "Y"}, {"family": "Erdelyi", "given": "Mate", "initials": "M", "orcid": "0000-0003-0359-5970", "researcher": {"href": "https://publications.scilifelab.se/researcher/f772b571449e417ca6fda2eee361a0c3.json"}}, {"family": "Schiesser", "given": "Stefan", "initials": "S", "orcid": "0000-0002-8668-2844", "researcher": {"href": "https://publications.scilifelab.se/researcher/c173ef3958eb49dea045b6962483b494.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}], "type": "journal article", "published": "2021-06-10", "journal": {"title": "ACS Med Chem Lett", "issn": "1948-5875", "volume": "12", "issue": "6", "pages": "983-990", "issn-l": "1948-5875"}, "abstract": "Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco-2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles' solution-phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderately flexible macrocycles, thereby contributing to the prioritization of macrocycles for synthesis in lead optimization.", "doi": "10.1021/acsmedchemlett.1c00126", "pmid": "34136079", "labels": {"Swedish NMR Centre": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC8201747"}], "notes": [], "created": "2021-07-02T14:05:55.552Z", "modified": "2025-10-17T13:03:55.774Z"}, {"entity": "publication", "iuid": "183a39b655614a3faef837da3a14521b", "links": {"self": {"href": "https://publications.scilifelab.se/publication/183a39b655614a3faef837da3a14521b.json"}, "display": {"href": "https://publications.scilifelab.se/publication/183a39b655614a3faef837da3a14521b"}}, "title": "Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs.", "authors": [{"family": "Danelius", "given": "Emma", "initials": "E", "orcid": "0000-0002-7322-9661", "researcher": {"href": "https://publications.scilifelab.se/researcher/738da5a280d04d3b9b1ced257b9ddb7f.json"}}, {"family": "Poongavanam", "given": "Vasanthanathan", "initials": "V", "orcid": "0000-0002-8880-9247", "researcher": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f.json"}}, {"family": "Peintner", "given": "Stefan", "initials": "S", "orcid": "0000-0001-9882-2018", "researcher": {"href": "https://publications.scilifelab.se/researcher/0583434982c84bd69f313f713744f5ed.json"}}, {"family": "Wieske", "given": "Lianne H E", "initials": "LHE", "orcid": "0000-0003-4617-7605", "researcher": {"href": "https://publications.scilifelab.se/researcher/9ee9a8547a194235a4d32170996b53e9.json"}}, {"family": "Erd\u00e9lyi", "given": "M\u00e1t\u00e9", "initials": "M", "orcid": "0000-0003-0359-5970", "researcher": {"href": "https://publications.scilifelab.se/researcher/f772b571449e417ca6fda2eee361a0c3.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}], "type": "journal article", "published": "2020-04-21", "journal": {"title": "Chemistry", "issn": "1521-3765", "volume": "26", "issue": "23", "pages": "5231-5244", "issn-l": "0947-6539"}, "abstract": "It has been hypothesised that drugs in the chemical space \"beyond the rule of 5\" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.", "doi": "10.1002/chem.201905599", "pmid": "32027758", "labels": {"Swedish NMR Centre": "Service"}, "xrefs": [], "notes": [], "created": "2020-12-11T09:13:45.140Z", "modified": "2025-10-17T13:03:56.989Z"}, {"entity": "publication", "iuid": "8d963319d34d4de9b6f1122d99d876b8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8d963319d34d4de9b6f1122d99d876b8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8d963319d34d4de9b6f1122d99d876b8"}}, "title": "Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?", "authors": [{"family": "Poongavanam", "given": "Vasanthanathan", "initials": "V", "orcid": "0000-0002-8880-9247", "researcher": {"href": "https://publications.scilifelab.se/researcher/d037f230665c490dada0a50ecc8c106f.json"}}, {"family": "Danelius", "given": "Emma", "initials": "E"}, {"family": "Peintner", "given": "Stefan", "initials": "S"}, {"family": "Alcaraz", "given": "Lilian", "initials": "L"}, {"family": "Caron", "given": "Giulia", "initials": "G", "orcid": "0000-0002-2417-5900", "researcher": {"href": "https://publications.scilifelab.se/researcher/c17599cc11164cbab6a07ed65817a9df.json"}}, {"family": "Cummings", "given": "Maxwell D", "initials": "MD"}, {"family": "Wlodek", "given": "Stanislaw", "initials": "S"}, {"family": "Erdelyi", "given": "Mate", "initials": "M", "orcid": "0000-0003-0359-5970", "researcher": {"href": "https://publications.scilifelab.se/researcher/f772b571449e417ca6fda2eee361a0c3.json"}}, {"family": "Hawkins", "given": "Paul C D", "initials": "PCD", "orcid": "0000-0001-9715-5049", "researcher": {"href": "https://publications.scilifelab.se/researcher/4ecced9fe9614233a48b125c682e6fdb.json"}}, {"family": "Ermondi", "given": "Giuseppe", "initials": "G", "orcid": "0000-0003-3710-3102", "researcher": {"href": "https://publications.scilifelab.se/researcher/bb03a62aa84c40489edb747571591110.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}], "type": "journal article", "published": "2018-09-30", "journal": {"title": "ACS Omega", "issn": "2470-1343", "volume": "3", "issue": "9", "pages": "11742-11757", "issn-l": "2470-1343"}, "abstract": "Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conformations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of a set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE-LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conformational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.", "doi": "10.1021/acsomega.8b01379", "pmid": "30320271", "labels": {"Swedish NMR Centre": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC6173504"}], "notes": [], "created": "2023-05-31T16:33:37.602Z", "modified": "2025-10-17T13:03:58.506Z"}]}