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Methods for drug discovery are being optimized in multiple ways to reduce costs and timelines. Crystallographic fragment screening (CFS) is increasingly being employed as an early screening method in drug discovery projects. Here, we demonstrate that selecting the optimal protein crystal form can significantly impact hit rates. Two CFS campaigns are carried out against the two crystal forms of the SARS\u2010CoV\u20102 main protease, using the same fragment library and an almost identical experimental setup. Although both crystal forms exhibit similar diffraction properties, the observed hit rates in the two campaigns differ significantly. A hit rate of 3% is determined for the monoclinic crystals, while a hit rate of 16% is observed for the orthorhombic crystals. These findings are consistent with the more open molecular packing in the orthorhombic crystals, where the solvent channels leading to the active sites are approximately twice the size of those in the monoclinic crystal form. Our results highlight the critical importance of the crystal form in a crystallographic screening, identifying it as one of the most important parameters to optimize when preparing a CFS campaign.<\/jats:p>","DOI":"10.1002\/smsc.202500484","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:39:17Z","timestamp":1772995157000},"source":"Crossref","is-referenced-by-count":1,"title":["Enhancing the Outcome of Crystallographic Fragment Screening by Choosing the Optimal Protein Crystal Form"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-3112","authenticated-orcid":false,"given":"Tatjana","family":"Barthel","sequence":"first","affiliation":[{"name":"Macromolecular Crystallography Helmholtz\u2010Zentrum Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Wollenhaupt","sequence":"additional","affiliation":[{"name":"Macromolecular Crystallography 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