Current Drug Targets - Volume 20, Issue 5, 2019

Anticancer peptide (ACP) is a kind of small peptides that can kill cancer cells without damaging normal cells. In recent years, ACP has been pre-clinically used for cancer treatment. Therefore, accurate identification of ACPs will promote their clinical applications. In contrast to labor-intensive experimental techniques, a series of computational methods have been proposed for identifying ACPs. In this review, we briefly summarized the current progress in computational identification of ACPs. The challenges and future perspectives in developing reliable methods for identification of ACPs were also discussed. We anticipate that this review could provide novel insights into future researches on anticancer peptides.

Background: Globally the number of cancer patients and deaths are continuing to increase yearly, and cancer has, therefore, become one of the world's highest causes of morbidity and mortality. In recent years, the study of anticancer drugs has become one of the most popular medical topics. Objective: In this review, in order to study the application of machine learning in predicting anticancer drugs activity, some machine learning approaches such as Linear Discriminant Analysis (LDA), Principal components analysis (PCA), Support Vector Machine (SVM), Random forest (RF), k-Nearest Neighbor (kNN), and Naïve Bayes (NB) were selected, and the examples of their applications in anticancer drugs design are listed. Results: Machine learning contributes a lot to anticancer drugs design and helps researchers by saving time and is cost effective. However, it can only be an assisting tool for drug design. Conclusion: This paper introduces the application of machine learning approaches in anticancer drug design. Many examples of success in identification and prediction in the area of anticancer drugs activity prediction are discussed, and the anticancer drugs research is still in active progress. Moreover, the merits of some web servers related to anticancer drugs are mentioned.

Molecular docking is a process through which small molecules are docked into the macromolecular structures for scoring its complementary values at the binding sites. It is a vibrant research area with dynamic utility in structure-based drug-designing, lead optimization, biochemical pathway and for drug designing being the most attractive tools. Two pillars for a successful docking experiment are correct pose and affinity prediction. Each program has its own advantages and drawbacks with respect to their docking accuracy, ranking accuracy and time consumption so a general conclusion cannot be drawn. Moreover, users don’t always consider sufficient diversity in their test sets which results in certain programs to outperform others. In this review, the prime focus has been laid on the challenges of docking and troubleshooters in existing programs, underlying algorithmic background of docking, preferences regarding the use of docking programs for best results illustrated with examples, comparison of performance for existing tools and algorithms, state of art in docking, recent trends of diseases and current drug industries, evidence from clinical trials and post-marketing surveillance are discussed. These aspects of the molecular drug designing paradigm are quite controversial and challenging and this review would be an asset to the bioinformatics and drug designing communities.

The largest family of drug targets in clinical trials constitute of GPCRs (G-protein coupled receptors) which accounts for about 34% of FDA (Food and Drug Administration) approved drugs acting on 108 unique GPCRs. Factors such as readily identifiable conserved motif in structures, 127 orphan GPCRs despite various de-orphaning techniques, directed functional antibodies for validation as drug targets, etc. has widened their therapeutic windows. The availability of 44 crystal structures of unique receptors, unexplored non-olfactory GPCRs (encoded by 50% of the human genome) and 205 ligand receptor complexes now present a strong foundation for structure-based drug discovery and design. The growing impact of polypharmacology for complex diseases like schizophrenia, cancer etc. warrants the need for novel targets and considering the undiscriminating and selectivity of GPCRs, they can fulfill this purpose. Again, natural genetic variations within the human genome sometimes delude the therapeutic expectations of some drugs, resulting in medication response differences and ADRs (adverse drug reactions). Around ~30 billion US dollars are dumped annually for poor accounting of ADRs in the US alone. To curb such undesirable reactions, the knowledge of established and currently in clinical trials GPCRs families can offer huge understanding towards the drug designing prospects including “off-target” effects reducing economical resource and time. The druggability of GPCR protein families and critical roles played by them in complex diseases are explained. Class A, class B1, class C and class F are generally established family and GPCRs in phase I (19%), phase II(29%), phase III(52%) studies are also reviewed. From the phase I studies, frizzled receptors accounted for the highest in trial targets, neuropeptides in phase II and melanocortin in phase III studies. Also, the bioapplications for nanoparticles along with future prospects for both nanomedicine and GPCR drug industry are discussed. Further, the use of computational techniques and methods employed for different target validations are also reviewed along with their future potential for the GPCR based drug discovery.

Enzymes are proteins that act as biological catalysts to speed up cellular biochemical processes. According to their main Enzyme Commission (EC) numbers, enzymes are divided into six categories: EC-1: oxidoreductase; EC-2: transferase; EC-3: hydrolase; EC-4: lyase; EC-5: isomerase and EC-6: synthetase. Different enzymes have different biological functions and acting objects. Therefore, knowing which family an enzyme belongs to can help infer its catalytic mechanism and provide information about the relevant biological function. With the large amount of protein sequences influxing into databanks in the post-genomics age, the annotation of the family for an enzyme is very important. Since the experimental methods are cost ineffective, bioinformatics tool will be a great help for accurately classifying the family of the enzymes. In this review, we summarized the application of machine learning methods in the prediction of enzyme family from different aspects. We hope that this review will provide insights and inspirations for the researches on enzyme family classification.

Membrane proteins play crucial physiological roles in vivo and are the major category of drug targets for pharmaceuticals. The research on membrane protein is a significant part in the drug discovery. The biological process is a cycled network, and the membrane protein is a vital hub in the network since most drugs achieve the therapeutic effect via interacting with the membrane protein. In this review, typical membrane protein targets are described, including GPCRs, transporters and ion channels. Also, we conclude network servers and databases that are referring to the drug, drug-target information and their relevant data. Furthermore, we chiefly introduce the development and practice of modern medicines, particularly demonstrating a series of state-of-the-art computational models for the prediction of drug-target interaction containing network-based approach and machine-learningbased approach as well as showing current achievements. Finally, we discuss the prospective orientation of drug repurposing and drug discovery as well as propose some improved framework in bioactivity data, created or improved predicted approaches, alternative understanding approaches of drugs bioactivity and their biological processes.

Ubiquitination is an important post-translational modification (PTM) process for the regulation of protein functions, which is associated with cancer, cardiovascular and other diseases. Recent initiatives have focused on the detection of potential ubiquitination sites with the aid of physicochemical test approaches in conjunction with the application of computational methods. The identification of ubiquitination sites using laboratory tests is especially susceptible to the temporality and reversibility of the ubiquitination processes, and is also costly and time-consuming. It has been demonstrated that computational methods are effective in extracting potential rules or inferences from biological sequence collections. Up to the present, the computational strategy has been one of the critical research approaches that have been applied for the identification of ubiquitination sites, and currently, there are numerous state-of-the-art computational methods that have been developed from machine learning and statistical analysis to undertake such work. In the present study, the construction of benchmark datasets is summarized, together with feature representation methods, feature selection approaches and the classifiers involved in several previous publications. In an attempt to explore pertinent development trends for the identification of ubiquitination sites, an independent test dataset was constructed and the predicting results obtained from five prediction tools are reported here, together with some related discussions.

Background: Ion channels are a large and growing protein family. Many of them are associated with diseases, and consequently, they are targets for over 700 drugs. Discovery of new ion channels is facilitated with computational methods that predict ion channels and their types from protein sequences. However, these methods were never comprehensively compared and evaluated. Objective: We offer first-of-its-kind comprehensive survey of the sequence-based predictors of ion channels. We describe eight predictors that include five methods that predict ion channels, their types, and four classes of the voltage-gated channels. We also develop and use a new benchmark dataset to perform comparative empirical analysis of the three currently available predictors. Results: While several methods that rely on different designs were published, only a few of them are currently available and offer a broad scope of predictions. Support and availability after publication should be required when new methods are considered for publication. Empirical analysis shows strong performance for the prediction of ion channels and modest performance for the prediction of ion channel types and voltage-gated channel classes. We identify a substantial weakness of current methods that cannot accurately predict ion channels that are categorized into multiple classes/types. Conclusion: Several predictors of ion channels are available to the end users. They offer practical levels of predictive quality. Methods that rely on a larger and more diverse set of predictive inputs (such as PSIONplus) are more accurate. New tools that address multi-label prediction of ion channels should be developed.

Background: Curcumin is a well-known pharmacophore and some of its derivatives are shown to target xanthine oxidase (XO) to alleviate disorders caused by the excess production of uric acid. Objective: Curcumin based derivatives were designed, synthesized and evaluated for their antioxidant and xanthine oxidase inhibitory potential. Method: In this report, we designed and synthesized two series of curcumin derivatives modified by inserting pyrazole and pyrimidine ring to central keto group. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. Results: Results showed that pyrazole analogues of curcumin produced excellent XO inhibitory potency with the IC50 values varying from 06.255 μM to 10.503 μM. Among pyrimidine derivatives compound CU3a1 having ortho nitro substitution exhibited more potent xanthine oxidase inhibitory activity than any other curcumin derivative of this series. Conclusion: Curcumin derivatives CU5b1, CU5b2, CU5b3, and CU3a1 showed a potent inhibitory activity against xanthine oxidase along with good antioxidant potential.