Multi-target QSAR modelling in the analysis and design of HIV-HCV co-inhibitors: an in-silico study
© Liu et al; licensee BioMed Central Ltd. 2011
Received: 13 December 2010
Accepted: 20 July 2011
Published: 20 July 2011
HIV and HCV infections have become the leading global public-health threats. Even more remarkable, HIV-HCV co-infection is rapidly emerging as a major cause of morbidity and mortality throughout the world, due to the common rapid mutation characteristics of the two viruses as well as their similar complex influence to immunology system. Although considerable progresses have been made on the study of the infection of HIV and HCV respectively, few researches have been conducted on the investigation of the molecular mechanism of their co-infection and designing of the multi-target co-inhibitors for the two viruses simultaneously.
In our study, a multi-target Quantitative Structure-Activity Relationship (QSAR) study of the inhibitors for HIV-HCV co-infection were addressed with an in-silico machine learning technique, i.e. multi-task learning, to help to guide the co-inhibitor design. Firstly, an integrated dataset with 3 HIV inhibitor subsets targeted on protease, integrase and reverse transcriptase respectively, together with another 6 subsets of 2 HCV inhibitors targeted on NS3 serine protease and NS5B polymerase respectively were compiled. Secondly, an efficient multi-target QSAR modelling of HIV-HCV co-inhibitors was performed by applying an accelerated gradient method based multi-task learning on the whole 9 datasets. Furthermore, by solving the L-1-infinity regularized optimization, the Drug-like index features for compound description were ranked according to their joint importance in multi-target QSAR modelling of HIV and HCV. Finally, a drug structure-activity simulation for investigating the relationships between compound structures and binding affinities was presented based on our multiple target analysis, which is then providing several novel clues for the design of multi-target HIV-HCV co-inhibitors with increasing likelihood of successful therapies on HIV, HCV and HIV-HCV co-infection.
The framework presented in our study provided an efficient way to identify and design inhibitors that simultaneously and selectively bind to multiple targets from multiple viruses with high affinity, and will definitely shed new lights on the future work of inhibitor synthesis for multi-target HIV, HCV, and HIV-HCV co-infection treatments.
Human immunodeficiency virus (HIV-1) is the cause of acquired immunodeficiency syndrome (AIDS) which has infected more than 60 million people around the world [1, 2]. Meanwhile, Hepatitis C virus (HCV), which is served as a serious cause of chronic liver disease, has infected 150-200 million people worldwide . Nowadays HIV and HCV infections have become global public-health threats. Even more remarkable, HIV-HCV co-infection is rapidly emerging as a major cause of morbidity and mortality throughout the world, since that both of the viruses share the same routes of transmission [3, 4]. It is shown that infection with the HCV is the most common co-infection in people with HIV, and hepatitis C is categorized as an HIV-related opportunistic illness. Complications related to HIV-HCV co-infection are becoming an increasingly important medical issue .
The current strategies for developing HIV/HCV antiviral agents depend essentially on disrupting the replication of the 2 viruses, and various inhibitors have been designed to target and block the functions of the enzymes necessary in the replication cycle of HIV/HCV. Among them, HIV inhibitors commonly target on protease, integrase and reverse transcriptase (RT), while HCV inhibitors target on NS5B polymerase and NS3 serine protease [5–18]. These inhibitors have been considered as attractive targets for therapeutic intervention in HIV/HCV infected patients.
For HIV and HCV therapy, single antiretroviral drug, alone or in simply combination with each other, is no longer recommended for clinical use owing to (1) the complicated infection mechanism of these two viruses; (2) the severe side effects of the joint using and (3) the rapid emergence of drug-resistant strains after initiation of therapy. Hence, drugs targeting on different targets with high therapeutic and reduced side effects are expected to be more effective at suppressing viral growth. For HIV, The multi-target antiretroviral drugs can succeed in inhibiting several HIV proteins simultaneously and efficiently. There has existed several pioneering work in multi-target drug discovery for HIV infection, such as the multi-target antiretroviral drug Cosalane , which was developed to inhibit several HIV-1 proteins simultaneously. Compared to HIV, the multiple target HCV drug treatment is still in its infancy. Nevertheless, the combination use of single-target HCV drugs has become a new chance in this field, such as the combination using of NS5B polymerase inhibitor (GS-9190) and NS3 protease inhibitor (GS-9256), which were shown to be safe, well-tolerated and show dose dependant antiviral activity [19, 20].
Since for both HIV and HCV the small-molecule compounds used to design the drugs are needed to be assayed in vitro and in vivo, the popular in-silico Quantitative Structure-Activity Relationship (QSAR) modelling is applied extensively in HIV/HCV inhibitor studies due to its charming "black-box" characteristics as well as its well prediction ability. Normally the QSAR modelling can be viewed as a computational technique to elucidate a quantitative correlation between chemical structure and biological activity . Recently, considerable QSAR studies have been made for HIV/HCV inhibitors studies [5–18]. However, these studies were mainly focused on specific types of targets or specific diseases individually. Few studies have been performed on the multi-target HIV-HCV co-infection QSAR modelling. Although the ways in which co-infection with HIV and HCV affect the body are still poorly understood, it has been indicated that both HIV-1 Protease and HCV NS3 Protease are responsible for cleaving the viral polyproteins during the course of their action to produce the individual proteins of the mature viruses. Similarly, HIV-1 reverse transcriptase and HCV NS5B can be affected by either nucleoside inhibitor that terminates nucleic acid synthesis or non-nucleoside inhibitor that impairs enzymatic function [22, 23]. All these evidences have indicated that it is possible to design certain inhibitors that aim at both HIV targets and HCV targets simultaneously. From this point of view, multi-target co-infection QSAR modelling for HIV and HCV is attractive and promising, due to that it is easy to achieve and expected to provide useful clues on how to synthesize such co-inhibitors with improved affinities.
In our previous study, we presented a multi-target QSAR modelling on HIV-1 inhibitors individually . In this study we desire to extend this model to investigate the multi-target QSAR modelling of HIV and HCV jointly and simultaneously, and aim at providing useful clues on the design of HIV-HCV co-inhibitors. The QSAR modelling of HIV-HCV co-infection inhibitors (co-inhibitors for short) was addressed by applying an efficient accelerated gradient method based multi-task learning (MTL) model provided by us formerly in machine learning community . QSAR studies were performed on 9 datasets of HIV and HCV inhibitors. By using our MTL framework, the correlations among different set of inhibitors were utilized and an efficient multi-target QSAR modelling of HIV-HCV co-inhibitors was obtained. According to the importance of each descriptor in QSAR model, the Drug-like index (DL) features  for inhibitor description were ranked, and a drug structure-activity simulation were performed to investigate the relationships between compound structures and binding affinities based on the ranked molecule descriptors.
Number of inhibitors
HIV-1 Reverse Transcriptase
HCV NS5B Polymerase
HCV NS5B Polymerase
HCV NS5B Polymerase
HCV NS3 Serine Protease
HCV NS3 Serine Protease
HCV NS3 Serine Protease
Similar to our previous study , the inhibitors were represented with 2 kinds of feature spaces referring to 32-dimensional General Descriptor (GD) features and 28-dimensional Drug-like index (DL) features. Although there are numerous types of descriptors to describe a chemical compound, none of a set of descriptors can guarantee to behave overwhelming better than others. Therefore, the widely applicable set of descriptors, i.e., the GD  was selected, together with the DL descriptor [26, 27] as a complement.
Detailed biological meaning of GD and DL descriptors can be referred in our previous work . It should be noted that: (1) normally, general descriptors characterize physical prosperities of compounds, while drug-like index descriptors characterize simple topological indices of compounds. These two kinds of descriptors are expected to present a comprehensive description of the compounds from the views of their intrinsic characteristics as well as their drug-like properties. (2) The GD descriptor is generated in a hybridized way thus its current features haven't kept their original means for compound structure description. Therefore it cannot be biologically explained easily. On the other side, DL holds its original meanings, thus will be applied in our following feature ranking and explanations.
Where [L] is the concentration of free radio ligand used and K D is its equilibrium dissociation constant for the receptor .
It should be noted that the QSAR data were provided by different research groups under different platforms/protocols with different activity measurements. Normally QSAR modeling achieved by such single target data is often not reliable due to the insufficiency of samples. However, since we want to investigate the multi-target QSAR relationship of the HIV-HCV co-infection, these data can be integrated in an elegant multi-target QSAR model taking the advantages of the multi-task learning , which would expect to exploit the possible synergies between different datasets and obtain a better QSAR model to guide the synthesis of certain inhibitors with enhanced activities for HIV and HCV simultaneously. Details will be shown in the following.
Computational framework for multi-target modelling
In current study, a novel accelerated gradient descent algorithm based MTL model was performed for multi-target QSAR modeling on our integrated datasets simultaneously. Our in-house experiments indicated that this MTL model is more efficient than our formerly adopted one for multi-target QSAR modeling  and it is scaled up well for large scale QSAR modeling in both convergence speed and learning accuracy. A joint L-1-infinity regularization based feature selection procedure was performed on the DL feature space to reveal the most common features across multi-target HIV-HCV co-infection QSAR modeling. Based on such model, a drug structure-activity simulation for investigating the relationships between compound structures and binding affinities was further presented to validate our selected important features for efficient co-inhibitor synthesis and design.
Multi-task learning for QSAR modelling of HIV-HCV co-inhibitors
Multi-task learning has been developed in machine learning research to situations where multiple related learning tasks are accomplished together. It has been proven to be more effective than learning each task independently when there are explicit or hidden interrelationship among the tasks that can be exploited. The intuition underlying the framework is that the multiple related tasks can benefit each other by sharing the data and features across the tasks, which can often boost the learning performance of each single task . Also it provides an efficient mechanism for cross-task feature selection, thus could uncover the common dominate features for all the tasks simultaneously. Such computational ability is inherently suitable for our multi-target QSAR modeling, in which each single QSAR model could be viewed as a task and the leading features for synthesizing co-inhibitors with improved activity will be identified under such schema.
It should be noted that the QSAR modelling is the process by which chemical structure is quantitatively correlated with a well-defined process, such as biological activity or chemical reactivity. And this procedure is generally formulated as a regression model  to predict the compound activity based on a given set of molecule descriptors. Although various statistical and machine learning methods have been proposed in the last few years for QSAR modeling , few studies have been tried in the multi-target QSAR scenario. In our study the multi-target QSAR modeling will be elegantly formulated as a multi-task regression framework to reveal useful clues for multi-target drug screening and synthesizing for HIV-HCV co-infections.
where z = (x, y, k), W =[w1, w2, ..., w M ] ∈ R d × M and W j be the j th row of W.
The first term in Equation (3) is the average of the empirical error across the tasks. The second term is the L-1-infinity regularization term that works on feature selection task in MTL, which can yield joint sparsity on both the feature level and task level and can lead to a more sparse solution .
As the main difficulty for solving the l1,∞ regularized formulation in formation (6) lies in the non-smooth property of the l1,∞ regularizer, we present an accelerated gradient descent algorithm with the convergence rate O (1/t2) by a variation of Nesterov's method calling a black-box oracle in the projection step at each iteration . By exploiting the structure of the l1,∞ ball, we find the black-box oracle can be efficiently solved by a simple sorting procedure. Compared with Nesterov's algorithm, our method is suitable for large-scale multi-task learning problem since it only utilizes the first order information and is very easy to implement. Experiment results in our previous study have shown that our method significantly outperforms the most state-of-the-art methods in both convergence speed and learning accuracy .
where ||·|| F denotes the Frobenius norm and 〈A, B〉 = Tr(A T B) denotes the matrix inner product.
Algorithm 1: Accelerated Gradient Algorithm
Initialization: L0 > 0, η > 1, W0 ∈ Rd × M, V0 = W0 and a0 = 1.
Set L = L t
While F(q L (V t )) > Q L (q L (V t ), V t )
We stop the procedure when κ ≤ τ where τ is a prefixed constant.
where W i , V i denotes the i th row of the matrix W, V respectively. Therefore, (10) can be decomposed into d separate subproblems of dimension M.
and the vector of dual variables α satisfies the relation α = v - w. Equation (12) can be solved by an efficient projection onto the ball l1 according to . With the primal dual relationship, we present Algorithm 2 for solving (11):
Algorithm 2: Algorithm for projection onto the l∞ ball
Let u i be the absolute value of v i , i.e. u i = |v i |. Sort vector u in the decreasing order: u 1 ≥ u 2 ≥ ... ≥ u M
Feature selection across multiple tasks
The value of β i indicates the weight of the corresponding feature, which gives us a quantitative way to evaluate the importance of various features for HIV-HCV co-inhibitor design and synthesize.
Domain of applicability of the model
Where X i is the row-vector descriptor of the query compound, X i is the n × k matrix containing k descriptor values and n training samples. The superscript T refers to the transpose of the matrix or vector. Generally, the warning leverage h* is fixed at 3 k/n, where n is the number of training compounds, and k is the number of descriptor. When a leverage is greater than the warning leverage h*, the predicted activity is the result of substantial extrapolation of the model and, therefore, it may not be reliable.
Based on the definition of leverage, Williams plot was used in our study to visualize the DOA of the QSAR model . The Williams plot plots the standardized cross-validated residuals (RES) versus leverage values (h), and can be used to obtain an immediate and simple graphical detection of both the response outliers (Y outliers) and the structurally influential chemicals (X outliers) of a model. Generally, the points with their values of Y axis fall outside the 3σ line (σ is the standard residuals unit of the compounds) can be referred as the Y outliers, while the points with their values of X axis fall outside the warning leverage h* line can be referred as the X outliers.
Multi-target HIV-HCV co-inhibitor design based on drug structure-activity prediction
After the feature ranking together with the examination of domain of application for multiple HIV-HCV drug targets QSAR modelling, a drug structure-activity prediction  was performed for the analysis of the multiple drug data. The goal of this study is two folds: (1) It is used to computationally validate the ranking result by our multi-task feature selection, and (2) It provides several useful modification strategies for further HIV-HCV co-inhibitor design.
Based on this computational prediction pipeline, we will identify what is the most efficient compound modification strategy to improve the molecule affinity targeting on multiple HIV-HCV enzymes. Also, these identified strategies will be further explained by our joint feature ranking obtained under the multi-target QSAR paradigm.
Results and Discussions
Formulated as a multi-task regression problem, the QSAR modelling of HIV-HCV co-inhibitors was performed based on the accelerated gradient descent based sparse multi-task learning. Root mean squared error (RMSE) and squared correlation coefficient (R2) were adopted as the performance evaluation for testing results. The definitions of these statistical parameters are provided as followed:
where n is the number of predicted drug molecules
y i is the observed molecule affinity
It is obvious that for both GD and DI feature space, using multi-task learning for QSAR modelling is superior to single-task learning on most target datasets, with the evaluation of RMSE and R2 and significant statistical confidence (data not shown). And the average correlation coefficient for data prediction under MTL is up to 0.6~0.7, which is a well-accepted QSAR results. Such results proved that multi-task learning can discover the latent commonalities across different types of inhibitors and take advantage of the synergy among multiple tasks when the label data on each single task are insufficient. These results also indicated that multi-task learning provides an effective way to boost the learning performance of each single task by exploiting the available synergy between them, thus served as an efficient paradigm for multi-target QSAR modelling.
After building the QSAR model, the weight of the DL features for MTL on 3 HIV datasets, 6 HCV datasets and all 9 datasets respectively were calculated, Sparse MTL in this case was trained with 50% of the data for each task and tested with the remaining data. The features ranking were showed in Figure 8, 9 and 10. It should be noted that the GD feature space will not be adopted for feature ranking due to its indirectly mapping of biological meanings.
A joint feature ranking of the DL compound descriptors.
# of non-H
# of 2-degree cyclic atoms
degree of cyclization
# of non-H polar bonds
# of rotatable bonds
# of carbons in cap fragments
# of cap fragments
# of 3-degree cyclic atoms
# of N and O atoms
# of H-bond acceptors
# of fragments
maximum cap fragment size
# of 2-degree acyclic atoms
# of 3-degree acyclic atoms
# of 3-level bonding patterns
total SSSR size
total number of 3-8 membered rings
# of cyclic fragments
# of 1-level bonding patterns
# of H-bond donors
total number of 3 to 8 unsaturated rings
# of aromatic systems
# of N with # of H > 0
# of hydroxyl groups
maximum SSSR size
# of linkers
# of 2-level bonding patterns
total number of 3 to 8 saturated rings
More # of non-H, # of non-H polar bonds and # of rotatable bonds could increase the potency of HIV Protease Inhibitors.
More # of 2-degree cyclic atoms, degree of cyclization and # of non-H polar bonds could increase the potency of HIV Reverse Transcriptase Inhibitors.
More # of non-H, # of 2-degree cyclic atoms, degree of cyclization and # of non-H polar bonds could increase the potency of HIV Integrase Inhibitors.
5 More # of non-H, # of non-H polar bonds and # of rotatable bonds could increase the potency of HCV NS5B Inhibitors.
More # of non-H, # of 2-degree cyclic atoms, degree of cyclization and # of non-H polar bonds could increase the potency of HCV NS3 Inhibitors.
It should be noted that these features are well be commonly important for the multiple scaffolds with each inhibiting an individual target derived from our MTL model, and they can be necessarily integrated together to guide the synthesis of a single scaffold against multiple targets, which guarantee that one individual compound could hold its co-inhibitor ability for both virus targets.
A Multi-target computational screening of HIV-HCV co-inhibitors with a MTL paradigm was carried out in our study. Compared to our previous work , it is improved mainly in two aspects: (1) It integrated both HIV and HCV data sources to enhance significantly the identification of lead inhibitors for HIV-HCV co-inhibitor drugs development. (2) A novel accelerated gradient descent algorithm based MTL model was incorporated into the multi-target QSAR modeling with more efficiency in both convergence speed and learning accuracy. In summary, the computational pipeline presented here provided an efficient way to identify and design inhibitors that simultaneously and selectively bind to multiple targets multiple viruses with high affinity.
Future researches on multi-target QSAR analysis could be done to address the compound description issue with more kinds of feature descriptors. Also the investigations on the integration and fusion mechanisms of multi-view feature spaces in compound representation could be conducted. Recently developed transfer learning technologies  in machine learning community may help to handle such cases efficiently. Furthermore, the underline mechanisms of HIV-HCV co-infection as well as the synthesis of the co-inhibitors based on our study are definitely worthy for long-term perusing.
The authors would like to thank Dr. Qiang Yang at Hong Kong University of Science and Technology for their suggestions. This work was supported in part by Project White Magnolia Funding, Shanghai (Grant No. 2010B127), Tongji Excellent Young Scientist Funding (Grant No. 2000219052), National Natural Science Foundation of China (Grant No. 30976611) and Research Fund for the Doctoral Program of Higher Education of China (Grant No.20100072120050)
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