{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T03:53:09Z","timestamp":1771041189724,"version":"3.50.1"},"reference-count":27,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2010,5,15]],"date-time":"2010-05-15T00:00:00Z","timestamp":1273881600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2010,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to \u201clock\u201d into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.<\/jats:p>","DOI":"10.1128\/jvi.02531-09","type":"journal-article","created":{"date-parts":[[2010,3,18]],"date-time":"2010-03-18T00:46:53Z","timestamp":1268873213000},"page":"5368-5378","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":105,"title":["Evaluating the Substrate-Envelope Hypothesis: Structural Analysis of Novel HIV-1 Protease Inhibitors Designed To Be Robust against Drug Resistance"],"prefix":"10.1128","volume":"84","author":[{"given":"Madhavi N. L.","family":"Nalam","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]},{"given":"Akbar","family":"Ali","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]},{"given":"Michael D.","family":"Altman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}]},{"given":"G. S. Kiran Kumar","family":"Reddy","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]},{"given":"Sripriya","family":"Chellappan","sequence":"additional","affiliation":[{"name":"Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850"}]},{"given":"Visvaldas","family":"Kairys","sequence":"additional","affiliation":[{"name":"Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850"}]},{"given":"Ays\u0327egu\u0308l","family":"O\u0308zen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"},{"name":"Polymer Research Center and Department of Chemical Engineering, Bogazici University, TR-34342 Bebek, Istanbul, Turkey"}]},{"given":"Hong","family":"Cao","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]},{"given":"Michael K.","family":"Gilson","sequence":"additional","affiliation":[{"name":"Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850"}]},{"given":"Bruce","family":"Tidor","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139"}]},{"given":"Tariq M.","family":"Rana","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]},{"given":"Celia A.","family":"Schiffer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm060666p"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja076558p"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21431"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2007.00514.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra025195"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/374569a0"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/aid.1992.8.153"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.6.2314-2321.2005"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00047a001"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0795-523"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0042-6822(03)00484-7"},{"key":"e_1_3_2_13_2","unstructured":"2008 report on the global AIDS epidemic. 2008"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9704098"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.7.2484"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00108a056"},{"key":"e_1_3_2_17_2","first-page":"1333","volume":"11","year":"2004","unstructured":"King, N. 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