Search for non-nucleoside inhibitors of HIV-1 reverse transcriptase using chemical similarity, molecular docking, and MM-GB/SA scoring

被引:72
作者
Barreiro, Gabriela [1 ]
Guimaraes, Cristiano R. W. [1 ]
Tubert-Brohman, Ivan [1 ]
Lyons, Theresa M. [1 ]
Tirado-Rives, Julian [1 ]
Jorgensen, William L. [1 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
关键词
D O I
10.1021/ci700271z
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A virtual screening protocol has been applied to seek non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and its K103N mutant. First, a chemical similarity search on the Maybridge library was performed using known NNRTIs as reference structures. The top-ranked molecules obtained from this procedure plus 26 known NNRTIs were then docked into the binding sites of the wild-type reverse transcriptase (HIV-RT) and its K103N variant (K103N-RT) using Glide 3.5. The top-ranked 100 compounds from the docking for both proteins were post-scored with a procedure using molecular mechanics and continuum solvation (MM-GB/SA). The validity of the virtual screening protocol was supported by (i) testing of the MM-GB/SA procedure, (ii) agreement between predicted and crystallographic binding poses, (iii) recovery of known potent NNRTIs at the top of both rankings, and (iv) identification of top-scoring library compounds that are close in structure to recently reported NNRTI HTS hits. However, purchase and assaying of selected top-scoring compounds from the library failed to yield active anti-HIV agents. Nevertheless, the highest-ranked database compound, S 10087, was pursued as containing a potentially viable core. Subsequent synthesis and assaying of S10087 analogues proposed by further computational analysis yielded anti-HIV agents with EC50 values as low as 310 nM. Thus, with the aid of computational tools, it was possible to evolve a false positive into a true active.
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页码:2416 / 2428
页数:13
相关论文
共 73 条
[1]   THE PETT SERIES, A NEW CLASS OF POTENT NONNUCLEOSIDE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE [J].
AHGREN, C ;
BACKRO, K ;
BELL, FW ;
CANTRELL, AS ;
CLEMENS, M ;
COLACINO, JM ;
DEETER, JB ;
ENGELHARDT, JA ;
HOGBERG, M ;
JASKUNAS, SR ;
JOHANSSON, NG ;
JORDAN, CL ;
KASHER, JS ;
KINNICK, MD ;
LIND, P ;
LOPEZ, C ;
MORIN, JM ;
MUESING, MA ;
NOREEN, R ;
OBERG, B ;
PAGET, CJ ;
PALKOWITZ, JA ;
PARRISH, CA ;
PRANC, P ;
RIPPY, MK ;
RYDERGARD, C ;
SAHLBERG, C ;
SWANSON, S ;
TERNANSKY, RJ ;
UNGE, T ;
VASILEFF, RT ;
VRANG, L ;
WEST, SJ ;
ZHANG, H ;
XHOU, XX .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995, 39 (06) :1329-1335
[2]   TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1 [J].
Andries, K ;
Azijn, H ;
Thielemans, T ;
Ludovici, D ;
Kukla, M ;
Heeres, J ;
Janssen, P ;
De Corte, B ;
Vingerhoets, J ;
Pauwels, R ;
de Béthune, MP .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2004, 48 (12) :4680-4686
[3]   PRECLINICAL EVALUATION OF MKC-442, A HIGHLY POTENT AND SPECIFIC INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN-VITRO [J].
BABA, M ;
SHIGETA, S ;
YUASA, S ;
TAKASHIMA, H ;
SEKIYA, K ;
UBASAWA, M ;
TANAKA, H ;
MIYASAKA, T ;
WALKER, RT ;
DECLERCQ, E .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1994, 38 (04) :688-692
[4]   Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy [J].
Bacheler, L ;
Jeffrey, S ;
Hanna, G ;
D'Aquila, R ;
Wallace, L ;
Logue, K ;
Cordova, B ;
Hertogs, K ;
Larder, B ;
Buckery, R ;
Baker, D ;
Gallagher, K ;
Scarnati, H ;
Tritch, R ;
Rizzo, C .
JOURNAL OF VIROLOGY, 2001, 75 (11) :4999-5008
[5]   From docking false-positive to active Anti-HIV agent [J].
Barreiro, Gabriela ;
Kim, Joseph T. ;
Guimares, Cristiano R. W. ;
Bailey, Christopher M. ;
Domaoal, Robert A. ;
Wang, Ligong ;
Anderson, Karen S. ;
Jorgensen, William L. .
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (22) :5324-5329
[6]   Virtual ligand screening against Escherichia coli dihydrofolate reductase:: Improving docking enrichment using physics-based methods [J].
Bernacki, K ;
Kalyanaraman, C ;
Jacobson, MP .
JOURNAL OF BIOMOLECULAR SCREENING, 2005, 10 (07) :675-681
[7]   Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: Past, present, and future perspectives [J].
Campiani, G ;
Ramunno, A ;
Maga, G ;
Nacci, V ;
Fattorusso, C ;
Catalanotti, B ;
Morelli, E ;
Novellino, E .
CURRENT PHARMACEUTICAL DESIGN, 2002, 8 (08) :615-657
[8]   Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent [J].
Campiani, G ;
Aiello, F ;
Fabbrini, M ;
Morelli, E ;
Ramunno, A ;
Armaroli, S ;
Nacci, V ;
Garofalo, A ;
Greco, G ;
Novellino, E ;
Maga, G ;
Spadari, S ;
Bergamini, A ;
Ventura, L ;
Bongiovanni, B ;
Capozzi, M ;
Bolacchi, F ;
Marini, S ;
Coletta, M ;
Guiso, G ;
Caccia, S .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (03) :305-315
[9]   2-amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1 [J].
Chan, JH ;
Hong, JS ;
Hunter, RN ;
Orr, GF ;
Cowan, JR ;
Sherman, DB ;
Sparks, SM ;
Reitter, BE ;
Andrews, CW ;
Hazen, RJ ;
St Clair, M ;
Boone, LR ;
Ferris, RG ;
Creech, KL ;
Roberts, GB ;
Short, SA ;
Weaver, K ;
Ott, RJ ;
Ren, JS ;
Hopkins, A ;
Stuart, DI ;
Stammers, DK .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (12) :1866-1882
[10]   Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors [J].
Corbett, JW ;
Ko, SS ;
Rodgers, JD ;
Gearhart, LA ;
Magnus, NA ;
Bacheler, LT ;
Diamond, S ;
Jeffrey, S ;
Klabe, RM ;
Cordova, BC ;
Garber, S ;
Logue, K ;
Trainor, GL ;
Anderson, PS ;
Erickson-Viitanen, SK .
JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (10) :2019-2030