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Two new species belonging to the varius group of Coccophagus, C. breviclavulus sp. nov. and C. perlucidus sp. nov., are described from Xishuangbanna Rainforest (China, Yunnan). Coccophagus anchoroides (Huang) and C. yunnana Wang, Huang & Polaszek are recorded. A tentative key to world species of this group is provided. Partial nuclear ribosomal 28S-D2 of these four species and other six species were sequenced and subjected to a phylogenetic analysis. Phylogeny of C. varius group is discussed. [ABSTRACT FROM AUTHOR]

The genus Eutrichosomella Girault is recorded for the first time from China (Yunnan Province), and Eutrichosomella yunnanensis sp. nov. (♀, ♂) is described and illustrated. A distribution map of this genus is presented. [ABSTRACT FROM AUTHOR]

Two new species of Paraphytis Compere, P. bannaensis sp. nov. and P. pseudovittatus sp. nov., are described from the Xishuangbanna Rainforest (Southwest China). A key to species from China based on females is provided. [ABSTRACT FROM AUTHOR]

In the present study, the effect of the heat shock protein 27 (HSP27) signaling pathway on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) induced by high glucose (HG) was investigated. HUVEC proliferation in the indicated conditions was measured by the alamarBlue® assay. Apoptosis in HUVECs cultured with HG was analyzed by an Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit. HSP27 activity was evaluated by western blotting with specific phospho-HSP27 antibody. HUVEC proliferation induced by HG was observed to be reduced by the HSP27 inhibitor quercetin in a concentration-dependent manner, with a concomitant increase in apoptosis. The phosphorylation of HSP27 induced by HG was blocked by the specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and the specific extracellular signal-regulated kinase (ERK) 1/2 inhibitor U0126 in a concentration-dependent manner, with peak inhibition rates of 62.6 and 56.1%, respectively. LY294002 and U0126 also reduced HUVEC proliferation with a concomitant increase in apoptotic rate. In conclusion, HSP27 phosphorylation is important in mediating the proliferation and apoptosis of HUVECs induced by high glucose, and PI3K/Akt and ERK1/2 are important signaling pathways that contribute to HSP27 phosphorylation. [ABSTRACT FROM AUTHOR]

Oil/water partition coefficient (log P) is one of the key points for lead compound to be drug. In silico log P models based solely on chemical structures have become an important part of modern drug discovery. Here, we report support vector machines, radial basis function neural networks, and multiple linear regression methods to investigate the correlation between partition coefficient and physico-chemical descriptors for a large data set of compounds. The correlation coefficient r 2 between experimental and predicted log P for training and test sets by support vector machines, radial basis function neural networks, and multiple linear regression is 0.92, 0.90, and 0.88, respectively. The results show that non-linear support vector machines derives statistical models that have better prediction ability than those of radial basis function neural networks and multiple linear regression methods. This indicates that support vector machines can be used as an alternative modeling tool for quantitative structure–property/activity relationships studies. [ABSTRACT FROM AUTHOR]

Background: Kinase-inducible domain (KID) as transcriptional activator can stimulate target gene expression in signal transduction by associating with KID interacting domain (KIX). NMR spectra suggest that apo-KID is an unstructured protein. After post-translational modification by phosphorylation, KID undergoes a transition from disordered to well folded protein upon binding to KIX. However, the mechanism of folding coupled to binding is poorly understood. Methodology: To get an insight into the mechanism, we have performed ten trajectories of explicit-solvent molecular dynamics (MD) for both bound and apo phosphorylated KID (pKID). Ten MD simulations are sufficient to capture the average properties in the protein folding and unfolding. Conclusions: Room-temperature MD simulations suggest that pKID becomes more rigid and stable upon the KIX-binding. Kinetic analysis of high-temperature MD simulations shows that bound pKID and apo-pKID unfold via a three-state and a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound pKID folds in the order of KIX access, initiation of pKID tertiary folding, folding of helix αB, folding of helix αA, completion of pKID tertiary folding, and finalization of pKID-KIX binding. Our data show that the folding pathways of apo-pKID are different from the bound state: the foldings of helices αA and αB are swapped. Here we also show that Asn139, Asp140 and Leu141 with large Φ-values are key residues in the folding of bound pKID. Our results are in good agreement with NMR experimental observations and provide significant insight into the general mechanisms of binding induced protein folding and other conformational adjustment in post-translational modification. [ABSTRACT FROM AUTHOR]

Two new steroidal saponins (1 and 2) were isolated from the dried bulbs of Allium macrostemon Bunge. Their structures were elucidated by the spectral data as 26-O- β-D-glucopyranosyl-5α-furost-25 (27)-ene-3β, 12β, 22, 26-tetraol-3-O-β-Dglucopyranosyl (1→2) [β-D-glucopyranosyl (1→3)]-β-D-glucopyranosyl (1→4)-β-Dgalactopyranoside (1) and 26-O-β-D-glucopyranosyl-5β-furost-20 (22)-25 (27)-dien-3β, 12β, 26-triol-3-O-β-D-glucopyranosyl (1→2)-β-D-galactopyranoside (2), respectively. Their cytotoxic activities on several cancer cell lines (MCF-7, NCI-H460, SF-268 and HepG2) were tested. 1 showed special cytotoxity on SF-268, while 2 showed cytotoxity on NCI-H460 and SF-268 cell lines, respectively. [ABSTRACT FROM AUTHOR]

In a previously made cross Brassica napus cv. Oro (2 n = 38) × Capsella bursa-pastoris (2 n = 4 x = 32), one F1 hybrid with 2 n = 38 was totally male sterile. The hybrid contained no complete chromosomes from C. bursa-pastoris, but some specific AFLP (amplified fragment length polymorphism) bands of C. bursa- pastoris were detected. The hybrid was morphologically quite similar to ‘Oro’ except for smaller flowers with rudimentary stamens but normal pistils, and showed good seed-set after pollination by ‘Oro’ and other B. napus cultivars. The fertility segregation ratios (3:1, 1:1) in its progenies indicated that the male sterility was controlled by a single recessive gene. In the pollen mother cells of the male sterile hybrid, chromosome pairing and segregation were normal. Histological sectioning of its anthers showed that the tapetum was multiple layers and was hypertrophic from the stage of sporogenic cells, and that the tetrads were compressed by the vacuolated and disaggregated tapetum and no mature pollen grains were formed in anther sacs, thus resulting in male sterility. The possible mechanisms for the production of the male sterile hybrid and its potential in breeding are discussed. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor kinase is relative to the progression of various types of cancers. In order to design anticancer drug, docking and support vector machines were used to guide CoMFA and CoMSIA for constructing optimal 3D-QSAR model. Additional descriptors, log P and HOMO, combined with several fields of CoMFA and CoMSIA, were introduced to construct models for the inhibitor of epidermal growth factor receptor kinase. The results show that the inclusion of log P and HOMO energy is meaningful for 3D-QSAR model. The validation of these models was testified by some structurally diverse compounds, which were not included in the CoMFA and CoMSIA models. The docking study and molecular dynamic simulation permit us to insight into the binding mode between ligand and EGFR kinase, and provide important information for structure-based drug design. The proposed approach can also be extended to other QSAR investigations. [ABSTRACT FROM AUTHOR]

Abstract   Capsella bursa-pastoris (L.) Medic (2n = 4x = 32) is a natural double-low (erucic acid Sclerotinia sclerotiorum. Hybridizations were carried out between two Brassica species viz. B. rapa (2n = 20) and B. napus (2n = 38) as female and C. bursa-pastoris as male parent to introduce these desirable traits into cultivated Brassica species. Majority of F1 plants resembled female parents in morphology and only a few expressed some characters of male parent, including the white petals. Based on cytological observation of somatic cells, the F1 plants were classified into five types: two types from the cross with B. rapa, type I had 2n = 27–29; type II had 2n = 20; three types from the crosses with B. napus, type III was haploids with 2n = 19; type IV had 2n = 29; type V had 2n = 38. One to two chromosomes of C. bursa-pastoris were detected in pollen mother cells (PMCs) of type I plant by genomic in situ hybridization (GISH), together with chromosomal segments in ovary cells and PMCs of some F1 plants. Amplified fragment length polymorphism (AFLP) bands specific for the male parent, novel for two parents and absent bands in Brassica parents were generated in majority of F1 plants, even in Brassica-types and haploids, indicating the introgressions at various levels from C. bursa-pastoris and genomic alterations following hybridization. Some Brassica-type progeny plants had reduced contents of erucic acid and glucosinolates associated with improved resistance to S. sclerotiorum. The cytological and molecular mechanisms behind these results are discussed. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulation was applied to investigate the metabolism mechanism for quinone analogues. Favourable hydrogen bonds between ligand and NQO1, and parallel orientation between ligand and flavin adenine dinucleotide could explain the difference of metabolism rate (in μmol/min/mg) for quinone analogues. This is consistent with the experimental observation ( Structure 2001;9:659–667). Then Support Vector Machines was used to construct quantitative structure–metabolism rate model. The model was evaluated by 14 test set compounds. Some descriptors selected by Support Vector Machine, were introduced into standard fields of three-dimensional quantitative structure–metabolism relationship to improve the statistical parameters of three-dimensional quantitative structure–metabolism relationship models. The results show that the inclusion of highest occupied molecular orbital and lowest unoccupied molecular orbital is meaningful for three-dimensional quantitative structure–metabolism relationship models. These in silico absorption, distribution, metabolism and excretion models are helpful in making quantitative prediction of their metabolic rates for new lead compounds before resorting in vitro and in vivo experimentation. [ABSTRACT FROM AUTHOR]

The MDM2 N-terminal domain can bind to the transactivation domain of p53 and downregulate its ability to activate transcription. It was found that binding with p53 stabilizes the MDM2 N-terminal domain. Thus the coupling between binding and folding is essential in the normal functional interactions between p53 and MDM2. We have performed explicit-solvent molecular dynamics simulations (MD) for both bound MDM2N and apo-MDM2 to study the interdependence of binding and folding in the p53-MDM2 complex. Kinetic analysis of high-temperature MD simulations shows that both bound MDM2N and apo-MDM2 unfold via a two-state process. Both kinetics and free energy landscape analyses indicate that bound MDM2 unfolds in the order of p53 unbinding, tertiary unfolding, and finally secondary structure unfolding. Our data show that the unfolding pathways are different between bound MDM2N and apo-MDM2: the unfolding order of unstable helices and tertiary contacts is reversed. Transition state analysis shows that the transition state of bound MDM2 is more nativelike and more heterogeneous than that of apo-MDM2. The predicted Φ-values suggest that the stable helices are more nativelike than other regions in both bound MDM2N and apo-MDM2. Within the stable helices, helix II in bound MDM2 is more nativelike than that in apo-MDM2. However, helix I and IV in bound MDM2 are less nativelike than those in apo-MDM2. [ABSTRACT FROM AUTHOR]

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 μM. The rationality of the method was validated by experimental results. [ABSTRACT FROM AUTHOR]

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1-G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1-G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7-G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9-G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia. [ABSTRACT FROM AUTHOR]

CCR5 is the key receptor of HIV-1 virus entry into host cells and it becomes an attractive target for antiretroviral drug design. To date, six types of CCR5 antagonist were synthesized and evaluated. To search more potent bio-active compounds, non-linear support vector machine was used to construct the relationship models for 103 oximino-piperidino-piperidine CCR5 antagonists. Then, comparative molecular field analysis and comparative molecular similarity indices analysis models were constructed after alignment with their common substructure. Twenty-one structural diverse compounds, which were not included in the support vector machine, comparative molecular field analysis, and comparative molecular similarity indices analysis models, validated these models. The results show that these models possess good predictive ability. When comparing between support vector machine and 3D-quantitative structure activity relationship models, the results obtained from these two methods are compatible. However, 3D-quantitative structure activity relationship model is significantly better than support vector machine model and previous reported pharmacophore model. These models can help us to make quantitative prediction of their bio-activities before in vitro and in vivo stages. [ABSTRACT FROM AUTHOR]

HIV-1 reverse transcriptase is a key enzyme playing an important role in the HIV-1 life cycle for the replication of the RNA genome into DNA form. Lys103Asn (K103N) mutant frequently is observed in HIV-1 reverse transcriptase. Therefore, a series of novel non-nucleoside reverse transcriptase inhibitors were designed and synthesized. In vitro experimental results show that diaryltriazine analogs have potent anti-HIV activity with moderate to high selectivity. In order to design anti-HIV drug, docking and molecular dynamics simulation were used to investigate the binding mode between ligand and HIV-1 reverse transcriptase. The results suggest that the analogs might have a similar interaction mechanism with HIV-1 reverse transcriptase. Then comparative molecular field analysis and comparative molecular similarity indices analysis were used to construct quantitative structure–activity models. These models were evaluated by eight test set compounds. These models are helpful in making quantitative prediction of their activity for new lead compounds before resorting in vitro and in vivo experimentation. [ABSTRACT FROM AUTHOR]

TIS11d tandem zinc finger (TZF) domain can bind the class II AU-rich element of target mRNA and regulate mRNA turnover by promoting or inhibiting degradation. NMR spectra show that TIS11dTZF undergoes a transition from disordered to well folded upon binding to Zn and mRNA. To gain an insight into the mechanism, we have performed explicit-solvent molecular dynamics simulations (MD) for both bound and apo-TIS11dTZF to study the interdependence of binding and folding in the mRNA-TIS11dTZF complex. These results are in qualitative agreement with NMR experiment. Furthermore, this method could be used to other study about protein folding upon ligand binding. [ABSTRACT FROM AUTHOR]

Retinoic acid inducible gene I (RIG-I) senses viral RNA5 and triggers innate antiviral responses through induction of type I IFN5 and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κBl. Rig-I is required for NF-κBactivity via regulating F4f-icbl expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-icbl mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-κBl by recruiting the ribosomal proteins [ribosomal protein L13 (Rp113) and Rpl8~ and rRNAS (18S and 285). Down-regulation of Rig-I or Rpll3 significantly reduces Nf-icbl and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κBsignaling and is involved in multiple biological processes in addition to host antivirus immunity. [ABSTRACT FROM AUTHOR]

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNFα activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85a regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. [ABSTRACT FROM AUTHOR]

The phosphotriesterase-like lactonase (PLL) enzymes in the amidohydrolase superfamily hydrolyze various lactones and exhibit latent phosphotriesterase activities. These enzymes serve as attractive templates for in vitro evolution of neurotoxic organophos-phates (OPs) with hydrolytic capabilities that can be used as bioremediation tools. Here, a thermostable PLL from Geobacillus kaustophilus HTA426 (GkaP) was targeted for joint laboratory evolution with the aim of enhancing its catalytic efficiency against OP pesticides. By a combination of site saturation mutagenesis and whole-gene error-prone PCR approaches, several improved variants were isolated. The most active variant, 26A8C, accumulated eight amino acid substitutions and demonstrated a 232-fold improvement over the wild-type enzyme in reactivity (Kcat/Km) for the OP pesticide ethyl-paraoxon. Concomitantly, this variant showed a 767-fold decrease in lactonase activity with δ-decanolactone, imparting a specificity switch of 1.8 x 105-fold. 26A8C also exhibited high hydrolytic activities (19- to 497-fold) for several OP pesticides, including parathion, diazinon, and chlorpyri-fos. Analysis of the mutagenesis sites on the GkaP structure revealed that most mutations are located in loop 8, which determines substrate specificity in the amidohydrolase superfamily. Molecular dynamics simulation shed light on why 26A8C lost its native lactonase activity and improved the promiscuous phosphotriesterase activity. These results permit us to obtain further insights into the divergent evolution of promiscuous enzymes and suggest that laboratory evolution of GkaP may lead to potential biological solutions for the efficient decontamination of neurotoxic OP compounds. [ABSTRACT FROM AUTHOR]

MicroRNAs are endogenous 23-25 nt RNAs that play important gene-regulatory roles in animals and plants. Recently, miR369-3 was found to upregulate translation of TNFα mRNA in quiescent (G0) mammalian cell lines. Knock down and immunofluorescence experiments suggest that microRNA-protein complexes (with FXR1 and AGO2) are necessary for the translation upregulation. However the molecular mechanism of microRNA translation activation is poorly understood. In this study we constructed the microRNA-mRNA-AGO2-FXR1 quadruple complex by bioinformatics and molecular modeling, followed with all atom molecular dynamics simulations in explicit solvent to investigate the interaction mechanisms for the complex. A combined analysis of experimental and computational data suggests that AGO2-FXR1 complex relocalize microRNA:mRNA duplex to polysomes in G0. The two strands of dsRNA are then separated upon binding of AGO2 and FXR1. Finally, polysomes may improve the translation efficiency of mRNA. The mutation research confirms the stability of microRNA-mRNA-FXR1 and illustrates importance of key residue of Ile304. This possible mechanism can shed more light on the microRNA- dependent upregulation of translation. [ABSTRACT FROM AUTHOR]

Amyloid fibrils are found in many fatal neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, type II diabetes, and prion disease. The VEALYL short peptide from insulin has been confirmed to aggregate amyloid-like fibrils. However, the aggregation mechanism of amyloid fibril is poorly understood. Here, we utilized molecular dynamics simulation to analyse the stability of VEALYL hexamer. The statistical results indicate that hydrophobic residues play key roles in stabilizing VEALYL hexamer. Single point and two linkage mutants confirmed that Val1, Leu4, and Tyr5 of VEALYL are key residues. The consistency of the results for the VEALYL oligomer suggests that the intermediate states might be trimer (3-0) and pentamer(3-2). These results can help us to obtain an insight into the aggregation mechanism of amyloid fibril. These methods can be used to study the stability of amyloid fibril from other short peptides. [ABSTRACT FROM AUTHOR]

Diaryltriazine (DATA) and diarylpyrimidine (DAPY) were two category inhibitors with highly potent activity for wild type (wt) and four principal mutant types (L100I, K103N, Y181C and Y188L) of HIV-1 reverse transcriptase (RT). We had revealed the drug-resistant mechanism of DATA analogue inhibitors with molecular dynamics simulation and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. In this work, we investigated the drug-resistant mechanism of DAPY analogue inhibitors. It was found that DAPY analogue inhibitors form more hydrogen bonds and hydrophobic contacts with wild type and mutants of HIV-1 RT than DATA inhibitors. This could explain that DAPY analogue inhibitors are more potent than DATA for the wild type and mutants of HIV-1 RT. Then, 3D-QSAR models were constructed for these inhibitors of wild type and four principal mutant types HIV-1 RT and evaluated by test set compounds. These combined models can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 RT inhibitors before resorting to in vitro and in vivo experiment. [ABSTRACT FROM AUTHOR]

A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2-18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 μM) could significantly promote the gene transcriptional function of nuclear receptor RXRα. While 7-9, 13, 14, and the new structure 1 (each at 20 μM) showed significant reduction in RXRα gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRα. [ABSTRACT FROM AUTHOR]

Four new metabolites, including three new oblongolides named C1, P1, and X1 (1-3) and 6-hydroxyphomodiol (10), along with eight known compounds - oblongolides B (4), C (5), D (6), O (7), P (8) and U (9), (3R,4aR,5S,6R)-6-hydroxy-5-methylramulosin (11), and (3R)-5-methylmellein (12) - were isolated from the endophytic fungal strain Phomopsis sp. XZ-01 of Camptotheca acuminate. Their structures were elucidated by spectroscopic analyses, including 1H- and 13C-NMR, 2D NMR (HSQC, HMBC, 1H-1H COSY and NOESY) and HR-FT-MS. Cytotoxic activities of these compounds were evaluated. Some of them showed weak selective activities. [ABSTRACT FROM AUTHOR]

Diaryltriazine inhibitors have highly potent and effective bioactivities for the wild type of HIV-1 reverse transcription. To design new drug of antimutant HIV-1 reverse transcriptase, the mechanism of drug resistance for four types of mutants was revealed. Molecular dynamics simulations suggest that Lys101, Leu100, Lys103, Tyr181, and Tyr188 are key residues. Different mutants of key residues may have different interaction modes and lead to different drug resistances. Then, CoMFA and CoMSIA methods were employed to construct 3D quantitative structure-activity relationship models. These models were evaluated by test set compounds. These models can be used to make quantitative prediction of their bioactivities for lead compounds before resorting to in vitro and in vivo experimentation. [ABSTRACT FROM AUTHOR]