In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations.

Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC50 and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R2 substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations.

A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor-enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents.

Computer-aided molecular design of highly potent HIV-1 RT inhibitors: 3D QSAR and molecular docking studies of efavirenz derivatives.

Ligand- and structure-based design approaches have been applied to an extended series of 74 efavirenz compounds effectively inhibiting wild type (WT) and mutant type (K103N) HIV-1 reverse transcriptase (RT). For ligand-based approach, three dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), were performed. The starting geometry of efavirenz was obtained from X-ray crystallographic data. The efavirenz derivatives were constructed and fully optimized by ab-initio molecular orbital method at HF/3-21G level. Reliable QSAR models for high predictive abilities were developed. Regarding WT and K103N inhibitions, CoMFA models with r2/cv = 0.651 and 0.678 and CoMSIA models with r2/cv = 0.662 and 0.743 were derived, respectively. The interpretation obtained from the models highlights different structural requirements for inhibition of WT and K103N HIV-1 RT. To elucidate potential binding modes of efavirenz derivatives in the binding pocket of WT and K103N HIV-1 RT, structure-based approach based on computational docking studies of selected efavirenz compounds were performed by using GOLD and FlexX programs. The results derived from docking analysis give additional information and further probe the inhibitor-enzyme interactions. The correlation of the results obtained from 3D QSAR and docking models validate each other and lead to better understanding of the structural requirements for the activity. Therefore, these integrated results are informative to provide key features and a helpful guideline for novel compound design active against HIV-1 RT.

3D-quantitative structure-activity relationships of HEPT derivatives as HIV-1 reverse transcriptase inhibitors, based on Ab initio calculations.

Comparative molecular field analysis (CoMFA) has been applied to a large set of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues. The starting geometry of HEPT was obtained from crystallographic data of HEPT/HIV-1 reverse transcriptase (RT) complexes. The structures of 101 HEPT derivatives were considered and fully optimized by ab initio molecular orbital calculations at the HF/3-21G level. The best CoMFA model is satisfactory in both statistical significance and predictive ability. It shows excellent, high predictive ability as r2cv = 0.858. The derived model indicates the importance of steric contributions (64.4%) as well as electrostatic interactions for the HIV-1 RT inhibition. In addition, steric and electrostatic contour maps from this analysis agree well with the experimentally observed trend that there are steric interactions between the side chain of HEPT and an aromatic ring of Tyr181. It is concluded that a moderately sized group at C5 enhances contact with Tyr181 enough to push it into a position which renders the protein nonfunctional, but a smaller group has insufficient steric requirements to do this and a larger group renders the ligand too large for the cavity. The mutation-induced resistance of reverse transcriptase is explained by this analysis. The obtained results not only lead to a better understanding of structural requirements of this set of compounds for the inhibition but also enable the suggestions for new and more potent drugs.

Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations.

The structure and the conformational behavior of the HIV-1 reverse transcriptase inhibitor, 11-cyclopropyl-5,11dihydro-4-methyl-6H-dipyrido[3,2-b2',3'-e][1,4]diazepin-6-one (nevirapine), is investigated by semiempirical (MNDO, AMI and PM3) method, ab initio at the HF/3-21G and HF/6-31G** levels and density functional theory at the B3LYP/6-31G** level. The fully optimized structure and rotational potential of the nitrogen and carbon bond in the cyclopropyl ring were examined in detail. A similar geometrical minimum is obtained from all methods which shows an almost identical structure to the geometry of the molecule in the complex structure with HIV-1 reverse transcriptase. To get some information on the structure in solution, NMR chemical shift calculations were also performed by a density functional theory at the B3LYP/6-31G** level, using GIAO approximation. The calculated 1H-NMR and 13C-NMR spectra for the energy minimum geometry agree well with the experimental results, which indicated that the geometry of nevirapine in solution is very similar to that of the molecule in the inhibition complex. Furthermore, the obtained results are compared to the conformational studies of other non-nucleoside reverse transcriptase inhibitors and reveal a common agreement of the non-nucleoside reverse transcriptase inhibitors. The specific butterfly-like shape and conformational flexibility within the side chain of the non-nucleoside reverse transcriptase inhibitors play an important role inducing conformational change of HIV-1 reverse transcriptase structure and are essential for the association at the inhibition pocket.

Three-dimensional quantitative structure-activity relationships study on HIV-1 reverse transcriptase inhibitors in the class of dipyridodiazepinone derivatives, using comparative molecular field analysis.

A three-dimensional quantitative structure-activity relationships (3D QSAR) method, Comparative Molecular Field Analysis (CoMFA), was applied to a set of dipyridodiazepinone (nevirapine) derivatives active against wild-type (WT) and mutant-type (Y181C) HIV-1 reverse transcriptase. The starting geometry of dipyridodiazepinone was taken from X-ray crystallographic data. All 75 derivatives, divided into a training set of 53 compounds and a test set of 22 molecules, were then constructed and full geometrical optimizations were performed, based on a semiempirical molecular orbital method (AM1). CoMFA was used to discriminate between structural requirements for WT and Y181C inhibitory activities. The resulting CoMFA models yield satisfactory predictive ability regarding WT and Y181C inhibitions, with r2 cv = 0.624 and 0.726, respectively. CoMFA contour maps reveal that steric and electrostatic interactions corresponding to the WT inhibition amount to 58.5% and 41.5%, respectively, while steric and electrostatic effects have approximately equal contributions for the explanation of inhibitory activities against Y181C. The contour maps high-light different characteristics for different types of wild-type and mutant-type HIV-1 RT. In addition, these contour maps agree with experimental data for the binding topology. Consequently, the results obtained provide information for a better understanding of the inhibitor-receptor interactions of dipyridodiazepinone analogs.

Quantitative structure-activity relationships and comparative molecular field analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors.

Quantitative structure-activity relationships (QSAR) and Comparative Molecular Field Analysis (CoMFA) have been applied in order to explain the structural requirements of HIV-1 reverse transcriptase (HIV-1 RT) inhibitory activity of TIBO derivatives on the MT-4 cells. The best QSAR model is satisfactory in both statistical significance and predictive ability. The derived structural descriptors indicate the importance of electronic contributions toward the HIV-1 RT inhibition of this class of compounds. However, it could not reveal any hydrophobic influence because of high collinearity between C2 and log P variables. In order to cope with steric interaction in the correlation, 3D-QSAR was performed using CoMFA. The obtained CoMFA model shows high predictive ability, rcv2 = 0.771, and clearly demonstrates its potential in the steric feature of the molecules through contour maps, explaining a majority (81.8%) of the variance in the data. Consequently, these results can be useful in identifying the structural requirements of TIBO derivatives and helpful for better understanding the HIV-1 RT inhibition. Eventually, they provide a beneficial basis to design new and more potent inhibitors of HIV-1 RT.