{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T22:27:58Z","timestamp":1786660078701,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,11]]},"group-title":"Biochemistry","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R35 GM152029"],"award-info":[{"award-number":["R35 GM152029"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Contemporary RNA-binding ligand collections are biased toward aromatic scaffolds, although it remains unclear whether this over-representation reflects an intrinsic requirement for productive RNA recognition or historical discovery bias. Here, using a modular \u201chost-guest\u201d ligand design strategy targeting the\n                  <jats:italic>env8<\/jats:italic>\n                  cobalamin (Cbl) riboswitch, we established a common molecular framework to directly evaluate whether aromaticity is fundamentally required for RNA binding. We synthesized a focused series of cyclic aliphatic \u03b2-axial Cbl derivatives, expanding the ligand library and enabling matched-pair comparisons to isolate the contribution of aromaticity to molecular recognition. Aliphatic ligands supported high-affinity RNA binding and regulatory activity comparable to aromatic analogues, with several derivatives exhibiting equal or greater affinity than their matched aromatic counterparts. Structural analyses revealed that aromatic and aliphatic ligands engage the same cryptic RNA binding site through distinct modes of molecular recognition, including nucleobase \u03c0-stacking and alternative van der Waals packing arrangements. Machine learning analyses further demonstrated that the physicochemical features associated with affinity extend beyond aromaticity itself and instead reflect a broader combination of shape, surface, heteroatom, and electronic properties. Together, these findings demonstrate that high-affinity RNA binding can arise from multiple structural and physicochemical solutions, suggesting that aromaticity is not uniquely privileged as a strategy for RNA-targeted ligand design and supporting broader exploration of underrepresented RNA-binding chemotypes.\n                <\/jats:p>","DOI":"10.64898\/2026.08.10.743988","type":"posted-content","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:50:21Z","timestamp":1786463421000},"source":"Crossref","is-referenced-by-count":0,"title":["Reimagining productive chemical space for RNA recognition beyond aromaticity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2519-6615","authenticated-orcid":false,"given":"Lukasz T.","family":"Olenginski","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dia","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8347-5498","authenticated-orcid":false,"given":"Aleksandra J.","family":"Wierzba","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA"},{"name":"BioFrontiers Institute, University of Colorado, Boulder, CO 80303-0596, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1384-6625","authenticated-orcid":false,"given":"Robert T.","family":"Batey","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081314550733000_2026.08.10.743988v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.004"},{"key":"2026081314550733000_2026.08.10.743988v1.2","doi-asserted-by":"crossref","unstructured":"Schneekloth, J. ; Pettersson, M . RNA as a Drug Target: The next Frontier for Medicinal Chemistry. 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