Supa Hannongbua

In-silico ADME models: a general assessment of their utility in drug discovery applications.

ADME prediction is an extremely challenging area as many of the properties we try to predict are a result of multiple physiological processes. In this review we consider how in-silico predictions of ADME processes can be used to help bias medicinal chemistry into more ideal areas of property space, minimizing the number of compounds needed to be synthesized to obtain the required biochemical/physico-chemical profile. While such models are not sufficiently accurate to act as a replacement for in-vivo or in-vitro methods, in-silico methods nevertheless can help us to understand the underlying physico-chemical dependencies of the different ADME properties, and thus can give us inspiration on how to optimize them. Many global in-silico ADME models (i.e generated on large, diverse datasets) have been reported in the literature. In this paper we selectively review representatives from each distinct class and discuss their relative utility in drug discovery. For each ADME parameter, we limit our discussion to the most recent, most predictive or most insightful examples in the literature to highlight the current state of the art. In each case we briefly summarize the different types of models available for each parameter (i.e simple rules, physico-chemical and 3D based QSAR predictions), their overall accuracy and the underlying SAR. We also discuss the utility of the models as related to lead generation and optimization phases of discovery research.

A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation

In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2:1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol(-1)) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol(-1)). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development.

Binding energy analysis for wild-type and Y181C mutant HIV-1 RT/8-Cl TIBO complex structures: Quantum chemical calculations based on the ONIOM method

Two‐layered and three‐layered ONIOM calculations were performed to compare the binding energies of 8‐Cl TIBO inhibitor when bound into the human immunodeficiency virus reverse transcriptase binding pocket and a Y181C variant. Both consisted of 20 residues within a radius of 15 Å. A combination of different methods [MP2/6‐31G(d), B3LYP/6‐31G(d,p), and PM3] were performed to take advantage of ONIOMs layering strategy analysis. The obtained results clearly indicate that the Y181C mutation reduces the binding affinity and stability of the inhibitor by approximately 8–9 kcal/mol as obtained from different combined MO:MO methods. Analyses regarding the energetic components of the interaction and deformation energies for 8‐Cl TIBO inhibitor upon binding were also examined extensively. Additional calculations involving the interaction energies between 8‐Cl TIBO with individual residues surrounding the binding pocket were performed at MP2/6‐31G(d,p) and B3LYP/6‐31G(d,p) levels of theory to gain more insight into the energetic differences of wild‐type and Y181C mutant type at the atomistic level. Proteins 2005.

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.

Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase--evidence from molecular dynamics simulations and MM-PBSA calculations.

The important role of the bridge water molecule in the binding of HIV-1 reverse transcriptase (RT) inhibitor complex was elucidated by molecular dynamics (MD) simulations using an MM-PBSA approach. Binding free energies and thermodynamic property differences for nevirapine bound to wild type and Y181C HIV-1 reverse transcriptase were investigated, and the results were compared with available experimental data. MD simulations over 3 ns revealed that the bridge water formed three characteristic hydrogen bonds to nevirapine and two residues, His235 and Leu234, in the binding pocket. The energetic derived model, which was determined from the consecutive addition of a water molecule, confirmed that only the contribution from the bridge water was essential in the binding configuration. Including this bridge water in the MM-PBSA calculations reoriented the binding energies from -32.20 to -37.65 kcal/mol and -28.07 to -29.82 kcal/mol in the wild type and Y181C HIV-1 RT, respectively. From the attractive interactions via the bridge water, His235 and Leu234 became major contributions. We found that the bridge water is the key in stabilizing the bound complex; however, in the Y181C RT complex this bridge water showed weaker hydrogen bond formation, lack of attractive force to nevirapine and lack of binding efficiency, leading to the failure of nevirapine against the Y181C HIV-1 RT. Moreover, the dynamics of Val179, Tyr181Cys, Gly190 and Leu234 in the binding pocket showed additional attractive energetic contributions in helping nevirapine binding. These findings that the presence of a water molecule in the hydrophobic binding site plays an important role are a step towards a quantitative understanding of the character of bridge water in enzyme-inhibitor binding. This can be helpful in developing designs for novel non-nucleoside HIV-1 RT inhibitors active against the mutant enzyme.

Structure-activity correlation study of HIV-1 inhibitors: Electronic and molecular parameters

SummaryQuantitative structure-activity relationships (QSARs) for 40 HIV-1 inhibitors, 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine and its derivatives, were studied. Fully optimized geometries, based on the semiempirical AM1 method, were used to calculate electronic and molecular properties of all compounds. In order to examine the relation between biological activities and structural properties, multiple linear regression models were employed. A suitable QSAR model was obtained, showing not only statistical significance, but also predictive ability. The significant molecular descriptors used were atomic charges of two substituted carbon atoms in the thymine ring, hydration energies and molar refractivities of the molecules. These descriptors allowed a physical explanation of electronic and molecular properties contributing to HIV-1 inhibitory potency.

Absorption and emission spectra of ultraviolet B blocking methoxy substituted cinnamates investigated using the symmetry-adapted cluster configuration interaction method

The absorption and emission spectra of ultraviolet B (UVB) blocking cinnamate derivatives with five different substituted positions were investigated using the symmetry-adapted cluster configuration interaction (SAC-CI) method. This series included cis- and trans-isomers of ortho-, meta-, and para-monomethoxy substituted compounds and 2,4,5-(ortho-, meta-, para-) and 2,4,6-(ortho-, para-) trimethoxy substituted compounds. The ground and excited state geometries were obtained at the B3LYP/6-311G(d) and CIS/D95(d) levels of theory. All the compounds were stable as cis- and trans-isomers in the planar structure in both the S(0) and S(1) states, except the 2,4,6-trimethoxy substituted compound. The SAC-CI/D95(d) calculations reproduced the recently observed absorption and emission spectra satisfactorily. Three low-lying excited states were found to be relevant for the absorption in the UV blocking energy region. The calculated oscillator strengths of the trans-isomers were larger than the respective cis-isomers, which is in good agreement with the experimental data. In the ortho- and meta-monomethoxy compounds, the most intense peak was assigned as the transition from next highest occupied molecular orbital (next HOMO) to lowest unoccupied molecular orbital (LUMO), whereas in the para-monomethoxy compound, it was assigned to the HOMO to LUMO transition. This feature was interpreted as being from the variation of the molecular orbitals (MOs) due to the different substituted positions, and was used to explain the behavior of the excited states of the trimethoxy compounds. The emission from the local minimum in the planar structure was calculated for the cis- and trans-isomers of the five compounds. The relaxation paths which lead to the nonradiative decay were also investigated briefly. Our SAC-CI calculations provide reliable results and a useful insight into the optical properties of these molecules, and therefore, provide a useful tool for developing UVB blocking compounds with regard to the tuning of the photoabsorption.

Defining the membrane disruption mechanism of kalata B1 via coarse-grained molecular dynamics simulations

Kalata B1 has been demonstrated to have bioactivity relating to membrane disruption. In this study, we conducted coarse-grained molecular dynamics simulations to gain further insight into kB1 bioactivity. The simulations were performed at various concentrations of kB1 to capture the overall progression of its activity. Two configurations of kB1 oligomers, termed tower-like and wall-like clusters, were detected. The conjugation between the wall-like oligomers resulted in the formation of a ring-like hollow in the kB1 cluster on the membrane surface. Our results indicated that the molecules of kB1 were trapped at the membrane-water interface. The interfacial membrane binding of kB1 induced a positive membrane curvature, and the lipids were eventually extracted from the membrane through the kB1 ring-like hollow into the space inside the kB1 cluster. These findings provide an alternative view of the mechanism of kB1 bioactivity that corresponds with the concept of an interfacial bioactivity model.

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.