CoMFA 3D-QSAR analysis of HIV-1 RT nonnucleoside inhibitors, TIBO derivatives based on docking conformation and alignment

HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside RT inhibitors (NNRTIs) and nucleoside analogues. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTI category, there is a set of inhibitors commonly referred to as TIBO inhibitors. Fifty TIBO inhibitors were used in the work to build 3-D QSAR models. The two known crystal structures of complexes are used to investigate and validate the docking protocol. The results show that the docking simulations reproduce the crystal complexes very well with RMSDs of approximately 1 A and approximately 0.6 A for 1REV and 1COU, respectively. The alignment of molecules and "active" conformation selection are the key to a successful 3D-QSAR model by CoMFA. The flexible docking (Autodock3) was used on determination of "active" conformation and molecular alignment, and CoMFA and CoMSIA were used to develop 3D-QSAR models of 50 TIBOs in the work. The 3D-QSAR models demonstrate a good ability to predict the activity of studied compounds (r2 = 0.972, 0.944, q2 = 0.704, 0.776). It is shown that the steric and electrostatic properties predicted by CoMFA contours can be related to the binding structure of the complex. The results demonstrate that the combination of ligand-based and receptor-based modeling is a powerful approach to build 3D-QSAR models.     

Receptor-independent 4D-QSAR analysis of a set of norstatine derived inhibitors of HIV-1 protease

A training set of 27 norstatine derived inhibitors of HIV-1 protease, based on the 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acid core (AHPBA), for which the -log IC(50) values were measured, was used to construct 4D-QSAR models. Five unique RI-4D-QSAR models, from two different alignments, were identified (q(2) = 0.86-0.95). These five models were used to map the atom type morphology of the lining of the inhibitor binding site at the HIV protease receptor site as well as predict the inhibition potencies of seven test set compounds for model validation. The five models, overall, predict the -log IC(50) activity values for the test set compounds in a manner consistent with their q(2) values. The models also correctly identify the hydrophobic nature of the HIV protease receptor site, and inferences are made as to further structural modifications to improve the potency of the AHPBA inhibitors of HIV protease. The finding of five unique, and nearly statistically equivalent, RI-4D-QSAR models for the training set demonstrates that there can be more than one way to fit structure-activity data even within a given QSAR methodology. This set of unique, equally good individual models is referred to as the manifold model.     

4D-QSAR analysis of a series of antifungal p450 inhibitors and 3D-pharmacophore comparisons as a function of alignment

A training set of 55 antifungal p450 analogue inhibitors was used to construct receptor-independent four-dimensional quantitative structure-activity relationship (RI 4D-QSAR) models. Ten different alignments were used to build the models, and one alignment yields a significantly better model than the other alignments. Two different methodologies were used to measure the similarity of the best 4D-QSAR models of each alignment. One method compares the residual of fit between pairs of models using the cross-correlation coefficient of their residuals of fit as a similarity measure. The other method compares the spatial distributions of the IPE types (3D-pharmacophores) of pairs of 4D-QSAR models from different alignments. Optimum models from several different alignments have nearly the same correlation coefficients, r(2), and cross-validation correlation coefficients, xv-r(2), yet the 3D-pharmacophores of these models are very different from one another. The highest 3D-pharmacophore similarity correlation coefficient between any pair of 4D-QSAR models from the 10 alignments considered is only 0.216. However, the best 4D-QSAR models of each alignment do contain some proximate common pharmacorphore sites. A test set of 10 compounds was used to validate the predictivity of the best 4D-QSAR models of each alignment. The "best" model from the 10 alignments has the highest predictivity. The inferred active sites mapped out by the 4D-QSAR models suggest that hydrogen bond interactions are not prevalent when this class of P450 analogue inhibitors binds to the receptor active site. This feature of the 4D-QSAR models is in agreement with the crystal structure results that indicate no ligand-receptor hydrogen bonds are formed.     

A simple clustering technique to improve QSAR model selection and predictivity: application to a receptor independent 4D-QSAR analysis of cyclic urea derived inhibitors of HIV-1 protease

A training set of 50 tetrahydropyrimidine-2-one based inhibitors of HIV-1 protease, for which the -log K(i) values were measured, was used to construct receptor independent 4D-QSAR models. A novel clustering technique was employed to facilitate and improve model selection as well as test set predictions. Following the manifold model theory, five unique models were chosen by the clustering algorithm (q(2) = 0.81-0.84). The models were used to map the atom type morphology of the inhibitor binding site of HIV-1 protease as well as to predict the potencies (-log K(i)) of 10 test set compounds. The rank-difference correlation coefficient was used to evaluate the quality of the test set predictions, which was improved from 0.39 to 0.68 when the clustering technique was applied. The set of five models, collectively, identify the important binding characteristics of the HIV protease receptor site. This study demonstrates that the selected simple clustering technique provides a discrete algorithm for model selection, as well as improving the quality of test set, or unknown, compound prediction as determined by the rank-difference correlation coefficient.     

Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic.

A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized. Phenylnorstatine [Pns; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] and the 2S diastereomer, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) were effective transition-state mimics, and incorporation of Pns-Pro or Apns-Pro at the P1-P1' site gave potent and specific HIV-1 protease inhibitors. In the inhibitory assays, the chemically synthesized [Ala67,95] HIV-1 protease was used.     

3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r ² ranging from 0.83 to 0.92 and q ² from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.     

HIV蛋白酶抑制剂——利迪链菌素的分子对接研究

用分子对接的方法, 对利迪链菌素的抗HIV蛋白酶活性进行了研究. 为了更准确地反映利迪链菌素分子与酶蛋白结合的情况, 充分考虑受体活性部位的柔性, 采用了FlexX(初步对接)和Flexidock(精确对接)分两步将配体与受体进行对接. 在初步对接中, 设计了不同的受体活性部位来考察是否有结合水分子参与抑制剂与酶的结合. 对一种作用方式已知的非肽类HIV蛋白酶抑制剂Aha006进行的对接研究显示, 分子模拟的结果与实际情况吻合得较好, 证明了本文所采用的方法的可靠性. 利迪链菌素与蛋白酶活性部位的对接结果显示, 配体分子与受体之间的结合没有结合水分子的参与, 两者通过5对氢键作用结合成为稳定的复合物. 利迪链菌素占据结合腔, 覆盖了蛋白酶的活性三联体Asp25-Thr26-Gly27, 从而起到抑制其生物活性的作用.     

Heterocyclic HIV-1 protease inhibitors

[formula: see text] A series of simple heterocyclic HIV-1 protease inhibitors were developed on the basis of size, shape, and electronic complementarity to the active site of the enzyme. The C2-symmetric heterocycles do not contain a transition-state isostere nor are they active site directed irreversible inhibitors; thus, they represent the success of a new design strategy. The first generation heterocycles inhibit the protease in the micromolar range, whereas control compounds show no bioactivity at the same concentrations.     

Binding of novel fullerene inhibitors to HIV-1 protease: insight through molecular dynamics and molecular mechanics Poisson–Boltzmann surface area calculations

The objectives of this study include the design of a series of novel fullerene-based inhibitors for HIV-1 protease (HIV-1 PR), by employing two strategies that can also be applied to the design of inhibitors for any other target. Additionally, the interactions which contribute to the observed exceptionally high binding free energies were analyzed. In particular, we investigated: (1) hydrogen bonding (H-bond) interactions between specific fullerene derivatives and the protease, (2) the regions of HIV-1 PR that play a significant role in binding, (3) protease changes upon binding and (4) various contributions to the binding free energy, in order to identify the most significant of them. This study has been performed by employing a docking technique, two 3D-QSAR models, molecular dynamics (MD) simulations and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) method. Our computed binding free energies are in satisfactory agreement with the experimental results. The suitability of specific fullerene derivatives as drug candidates was further enhanced, after ADMET (absorption, distribution, metabolism, excretion and toxicity) properties have been estimated to be promising. The outcomes of this study revealed important protein–ligand interaction patterns that may lead towards the development of novel, potent HIV-1 PR inhibitors.     

基于分子对接的6-萘甲基取代HEPT类HIV-1逆转录酶抑制剂构效关系研究

采用分子对接方法得到了一系列6-萘甲基取代HEPT类逆转录酶抑制剂分子与HIV-1逆转录酶复合物模型,从中抽取出抑制剂分子的活性构象,进一步应用CoMFA和CoMSIA方法建立了具有较好预测能力的3D-QSAR模型,深入探讨了这些化合物的定量构效关系,为进一步的药物设计奠定了良好的基础.另外,以化合物13及其相应的β异构体24为代表,结合量子化学从头算分子轨道理论方法考察了它们的前线轨道,为阐明α和β系列化合物的活性差异提供了理论依据.     

Homology model-guided 3D-QSAR studies of HIV-1 integrase inhibitors

In the present study, we report the exploration of binding modes of potent HIV-1 integrase (IN) inhibitors MK-0518 (raltegravir) and GS-9137 (elvitegravir) as well as chalcone and related amide IN inhibitors we recently synthesized and the development of 3D-QSAR models for integrase inhibition. Homology models of DNA-bound HIV-1 IN were constructed on the basis of the X-ray crystal structure of the foamy virus IN-DNA complex (PDB ID: 3L2T ) and used for docking. The binding modes of raltegravir and elvitegravir in our homology models are in accordance with those in the foamy virus structure revealing interactions important for inhibitor-IN binding. To gain further insights into the structural requirements for IN inhibition, three-dimensional quantitative structure activity relationship (3D-QSAR) studies were conducted using raltegravir, elvitegravir, and their analogs; our synthesized 3-keto salicylic acid IN inhibitor series; as well as other structurally related HIV-1 IN inhibitors. In the first part of the study with 103 compounds, atom-fit alignments, I and II, and docking-based alignment, III, were used to develop 3D-QSAR models 1, 2, and 3, respectively, each comprising comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSARs. This initial analysis indicated that the docking-based (structure-based) model 3 performed better than the atom-fit (ligand-based) models 1 and 2, in terms of statistical significance and robustness. Thus, the docking-based alignment was then subsequently used with an expanded data set of 296 compounds for building a more comprehensive 3D-QSAR, model 4. Model 4 afforded good q2 values of 0.70 and 0.75 for CoMFA and CoMSIA 3D-QSARs, respectively, and showed good predictive performance on an external validation test set of 59 compounds with predictive r2 values up to 0.71. The HIV IN-DNA homology model of biological relevance and the comprehensive 3D-QSAR models developed in the present study provide insights and new predictive tools for structure-based design and optimization of IN inhibitors.     

4D-QSAR analysis of a set of ecdysteroids and a comparison to CoMFA modeling.

The ecdysteroid-responsive Drosophila melanogaster B(II) cell line is a prototypical homologous inducible gene expression system. A training set of 71 ecdysteroids, for which the -log(EC(50)) potencies in the ecdysteroid-responsive B(II) cell line were measured, was used to construct 4D-QSAR models. Four nearly equivalent optimum 4D-QSAR models, for two modestly different alignments, were identified (Q(2) = 0.76-0.80). These four models, together with two CoMFA models, were used in consensus modeling to arrive at a three-dimensional pharmacophore. The C-2 and C-22 hydroxyls are identified as hydrogen-bond acceptor sites which enhance activity. A hydrophobic site near C-12 is consistent with increasing activity. The side-chain substituents at C-17 are predicted to adopt semiextended "active" conformations which could fit into a cylinder-shaped binding pocket lined largely with nonpolar residues for enhanced activity. A test set of 20 ecdysteroids was used to evaluate the QSAR models. Two 4D-QSAR models for one alignment were identified to be superior to the others based on having the smallest average residuals of prediction for the prediction set (0.69 and 1.13 -log[EC(50)] units). The correlation coefficients of the optimum 4D-QSAR models (R(2) = 0.87 and 0.88) are nearly the same as those of the best CoMFA model (R(2) = 0.92) determined for the same training set. However, the cross-validation correlation coefficient of the CoMFA model is less significant (Q(2) = 0.59) than those of the 4D-QSAR models (Q(2) = 0.80 and 0.80).     

Comparison of azacyclic urea A-98881 as HIV-1 protease inhibitor with cage dimeric N-benzyl 4-(4-methoxyphenyl)-1,4- dihydropyridine as representative of a novel class of HIV-1 protease inhibitors: A molecular modeling study

The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxymethyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cyclic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concerning their orientation in space as well as in the enzyme HIV-1 protease. Starting from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl derivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was performed for the conformationally important torsion angles considering electrostatic and van der Waals interactions. From the huge number of conformations those comprising centrosymmetrical and C2-symmetrical energy minima were selected and minimized. The three remaining conformers were fitted to the azacyclic urea A-98881 selected from the HIV-1 protease enzyme- inhibitor complex using the centroids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energetically most favourable one, which, additionally, possesses C2-symmetry like the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the extent of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A- 98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O– of COO–), representing the decisive functional groups of the active site, have been calculated using GRID and projected into the enzyme placing the structures according to the position of A-98881 in the enzyme- inhibitor complex. The strongest calculated fields of the O– probe were found near Asp 25 for both structures. Another respective conformity consists in the overlap of the fields for the NHamide probe near Ile 50 and 50 for the investigated cage dimer and A-98881.     

Application of 4D-QSAR studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators

Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.0 ?). The QSAR equations, generated by a combined scheme of genetic algorithms (GA) and partial least squares (PLS) regression, were evaluated by "leave-one-out" cross-validation, using a training set of 41 compounds. External validation was performed using a test set of 13 compounds. The obtained 4D-QSAR models are in agreement with the proposed mechanism of action for raloxifene. This study allowed a quantitative prediction of compounds' potency and supported the design of new raloxifene analogs.     

Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere

We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179).     

Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study

We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC₅₀ values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.