Smith Marilyn B Kroeger, Rader Lenea H, Franklin Amanda M, Taylor Emily V, Smith Katie D, Smith Richard H, Tirado-Rives Julian, Jorgensen William L
Department of Chemistry, McDaniel College, Westminster, MD 21157, USA.
Bioorg Med Chem Lett. 2008 Feb 1;18(3):969-72. doi: 10.1016/j.bmcl.2007.12.033. Epub 2007 Dec 23.
The effect of mutations on amino acid residues L100, V106, and Y181 for unbound HIV-1 reverse transcriptase (RT) and RT bound to nevirapine and efavirenz was investigated using Monte Carlo/free energy perturbation calculations. Using both native and bound crystal structures of RT, mutation of the amino acid residues to both those observed and unobserved in patients was carried out. The results of the calculations revealed that the variant that survives in patients dosed with either nevirapine or efavirenz had a more positive Delta Delta G value than other variants that were not observed in patients. These data suggest that the mutation observed in patients is the most effective (the one that binds the drug most weakly) of all possible codon change mutations.
利用蒙特卡罗/自由能微扰计算方法，研究了突变对未结合的HIV-1逆转录酶（RT）以及与奈韦拉平或依非韦伦结合的RT中氨基酸残基L100、V106和Y181的影响。使用RT的天然和结合晶体结构，将氨基酸残基突变为患者中观察到的和未观察到的氨基酸。计算结果表明，在接受奈韦拉平或依非韦伦治疗的患者中存活的变体比在患者中未观察到的其他变体具有更正的ΔΔG值。这些数据表明，在患者中观察到的突变是所有可能的密码子变化突变中最有效的（即与药物结合最弱的）。
