Pornpan Pungpo

Investigating the structural basis of arylamides to improve potency against M. tuberculosis strain through molecular dynamics simulations

Arylamides have been identified as direct InhA inhibitors which overcome the drug-resistance problem of isoniazid, the first-line drug for tuberculosis treatment. However, arylamide properties are not yet optimal against Mycobacterium tuberculosis. Arylamides show high potency in InhA enzyme assay, but they fail in antimycobacterial assay. To achieve the structural basis to improve antimycobacterial activity, the dynamic behavior of arylamide inhibitors and a substrate, trans-2-hexadecenoyl-(N-acetylcysteamine)-thioester, were carried out by molecular dynamics (MD) simulations. Arylamide inhibitors and a substrate are positioned at the same site which indicates the competitive inhibitor function of arylamides. Based on our findings, the amide carbonyl oxygen causes the selectivity of arylamide inhibitors for InhA inhibition. Moreover, this moiety is crucial for the affinity of the arylamide-InhA interactions with Tyr158 and NADH to form hydrogen bonds. It is possible to enhance the selectivity of arylamide inhibitors to reach the InhA target by introducing a hydrophilic substituent into the aryl ring A. In order to increase the membrane permeability of arylamide inhibitors, more lipophilic properties should be incorporated into the substituent B. Therefore, based on the obtained results, the correct balance between the selectivity and the membrane permeability of arylamide inhibitors should improve their inhibitory activity against M. tuberculosis strain.

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.

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-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b2′,3′-e][1,4]diazepin-6-one (nevirapine), is investigated by semiempirical (MNDO, AM1 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.

Hologram Quantitative Structure-Activity Relationships Investigations of Non-nucleoside Reverse Transcriptase Inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT and dipyridodiazepinone are effective against HIV-1 RT. These NNRTIs are chemically and structurally diverse, but they all bind to a common allosteric site of HIV-1 RT. These inhibitors exhibit high potency, low cytotoxicity and produce few side effects. However, the emergency of drug-resistance viral strain has limited the therapeutic efficiency of the NNRTIs. Several different QSAR studies were reported to identify important structural features responsible for the inhibitory activity of these NNRTIs. In this study, hologram quantitative structure-activity relationships (HQSAR) was applied to three different data sets, 70 TIBO, 101 HEPT and 125 dipyridodiazepinone derivatives. Starting geometries of compounds were taken from available X-ray crystallographic data. Modification and full geometry optimization of all derivatives were performed, based on quantum chemical calculations at the HF/3-21G level of theory. All derived HQSAR models produce satisfying predictive ability and yield r(2)(cv) values ranging from 0.62-0.84. Moreover, it was also found that the quality of models enhances as the size of fragments increases. The obtained HQSAR results indicate the similarity of the interactions of these three different NNRTIs with the inhibition pocket of the enzyme. Comparisons of different QSAR methods on these NNRTIs data sets were also considered and it could be shown that HQSAR results yield superior predictive models than other 2D-QSAR approaches. In particular, the predictive ability of the models derived from dipyridodiazepinone analogues was significantly improved and apparently revealed differentiating structural requirements between WT and Y181C HIV RT inhibition. Additionally, the quality of QSAR models constructed by CoMFA and HQSAR methods are comparable and the interpretations of the models reinforce each other. It suggests an advantage of HQSAR as a useful tool in designing new potent inhibitors with enhanced HIV-1 RT inhibition activity, especially against mutant enzyme.

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  = 0.651 and 0.678 and CoMSIA models with  = 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.

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.

Recent Advances in NNRTI Design: Computer-Aided Molecular Design Approaches

Reverse transcriptase (RT), an essential enzyme for HIV-1 (human immunodeficiency virus type-1) life cycle, is a key target in drug discovery efforts against HIV-1 infection. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are very specific to HIV-1 RT and have relatively less toxicity than the nucleoside reverse transcriptase inhibitors (NRTIs). However, the rapid emergence of drug-resistant viral strains has limited the therapeutic efficacy of these inhibitors. In this review, recent advances in computer-aided drug design (CADD) for design of new compounds against HIV-1 RT based on ligand-based drug design (LBDD) using 2D-and 3D-QSAR approaches, structure-based drug design (SBDD) with the combination of molecular docking, virtual screening and de novo drug design, molecular simulations and particular interaction calculated from quantum chemical calculations are discussed. Their successful applications are also highlighted.

Elucidating Drug-Enzyme Interactions and Their Structural Basis for Improving the Affinity and Potency of Isoniazid and Its Derivatives Based on Computer Modeling Approaches

The enoyl-ACP reductase enzyme (InhA) from M. tuberculosis is recognized as the primary target of isoniazid (INH), a first-line antibiotic for tuberculosis treatment. To identify the specific interactions of INH-NAD adduct and its derivative adducts in InhA binding pocket, molecular docking calculations and quantum chemical calculations were performed on a set of INH derivative adducts. Reliable binding modes of INH derivative adducts in the InhA pocket were established using the Autodock 3.05 program, which shows a good ability to reproduce the X-ray bound conformation with rmsd of less than 1.0 Å. The interaction energies of the INH-NAD adduct and its derivative adducts with individual amino acids in the InhA binding pocket were computed based on quantum chemical calculations at the MP2/6-31G (d) level. The molecular docking and quantum chemical calculation results reveal that hydrogen bond interactions are the main interactions for adduct binding. To clearly delineate the linear relationship between structure and activity of these adducts, CoMFA and CoMSIA models were set up based on molecular docking alignment. The resulting CoMFA and CoMSIA models are in conformity with the best statistical qualities, in which r2cv is 0.67 and 0.74, respectively. Structural requirements of isoniazid derivatives that can be incorporated into the isoniazid framework to improve the activity have been identified through CoMFA and CoMSIA steric and electrostatic contour maps. The integrated results from structure-based, ligand-based design approaches and quantum chemical calculations provide useful structural information facilitating the design of new and more potentially effective antitubercular agents as follow: the R substituents of isoniazid derivatives should contain a large plane and both sides of the plane should contain an electropositive group. Moreover, the steric and electrostatic fields of the 4-pyridyl ring are optimal for greater potency.

Insight into the structural requirements of aminopyrimidine derivatives for good potency against both purified enzyme and whole cells of M. tuberculosis: combination of HQSAR, CoMSIA, and MD simulation studies

The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 < .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC > 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure–activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure–activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells.

Elucidating structural basis of benzofuran pyrrolidine pyrazole derivatives for enhancing potency against both the InhA enzyme and intact M. tuberculosis cells: a combined MD simulations and 3D-QSAR study

A 2-trans enoyl-acyl carrier protein (ACP) reductase or InhA of M. tuberculosis is a drug target of isoniazid (INH), the first-line drug for tuberculosis treatment. Many series of compounds have been developed as novel inhibitors of this enzyme. However, they lack good potency against purified InhA and activity against intact M. tuberculosis cells. Benzofuran pyrrolidin pyrazole derivatives are potent direct InhA inhibitors. These compounds show high potency for InhA inhibition with IC50 values at nanomolar levels. However, their activities against M. tuberculosis cells in terms of MIC90 were about one-thousand fold than IC50. Accordingly, in this work, IC50 and MIC90 values of benzofuran pyrrolidin pyrazole derivatives were subjected to CoMFA and CoMSIA studies in order to investigate the structural basis required for good activity against both purified InhA and M. tuberculosis cells. Moreover, MD simulations were employed to evaluate key interactions for binding benzofuran pyrrolidin pyrazole derivatives in InhA. Based on MD results, the core structure of these compounds is the key portion for binding in the InhA pocket. Alternatively, R substituents showed weak interactions with the InhA pockets. Interpretation of IC50 and MIC90 CoMSIA contour maps revealed the structural requirements in terms of steric, electrostatic, hydrophobic and hydrogen donor and acceptor for IC50 and MIC90 values of InhA inhibitors. Finally, the integrated results obtained from MD simulations and graphic interpretation of CoMSIA models provided a structural concept for rational design of novel InhA inhibitors with better potency against both the InhA enzyme and intact M. tuberculosis cells.