Current Pharmaceutical Design - Volume 18, Issue 9, 2012

Background: Neurodegenerative disorders (NDs) are typically referred to Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis and prion disease. These are commonly debilitating and, unfortunately, have few therapeutic options. Objective: In this review, we describe some emerging advances in nanoengineering strategies for the treatment of NDs. One of the main difficulties in fighting against NDs is to overcome the shielding of blood-brain barrier (BBB), which greatly limits the penetration of various therapeutic drugs, which sometimes leads to severe side effects. Nanotechnology, by engineering materials of a size scale usually within 1-100 nm, fortunately offers an alternative approach for novel, promising and innovative solutions. Nanoparticles are capable of not only penetrating the BBB but also releasing active ingredients at a specific site due to its surface functionalization. Therefore, nanoengineered delivery systems potentially facilitate the targeted delivery of neuronal therapeutic drugs and genes to the central nervous system. Furthermore, recently developed nanomaterials are considered as therapeutic agents themselves since they exhibit important roles in promoting the protection of healthy neurons or the regeneration of neurons to repair damaged tissues. Conclusion: There have been a variety of innovative approaches to designing therapeutic nanoparticles for NDs, and each has been associated with certain pros and cons.

Background: The association of pathogenic viruses with obesity has now been well-known in both human and animals. Globally, human obesity has become a serious problem leading to the emergence of multiple lifethreatening diseases. Adenoviruses contribute a significant role in the induction of obesity by affecting various pathways. Due to impaired immunity, obese individuals are more prone to nosocomial infections leading to complications of obesity. In contrast, several other important factors contributing to human obesity are known. Methods: Currently, many published reports showed strong evidence of the role and linkage of Ad36 infection in human obesity. The Ad36 pathogenesis effect on the hepatic steatosis reduces leptin gene expression, reduced antibody response in vaccination, reduces immune system, insulin sensitivity, increases glucose uptake, activates the lipogenic and pro-inflammatory pathways in adipose tissue increases the level of Macrophage Chemo attractant Protein-1 leading chronic inflammation and affect lipid metabolism. Results: The E4-ORF1 gene of Ad36 play an important role in the induction of adipogenesis and regulation of adipocyte differentiation and also known to activate the sensitizing effect of insulin. The use of E4-ORF1gene as a ligand to develop new drugs against diabetes and the prevention of Ad36 infection by an effective vaccination will attract researchers and open new area of research in the field of obesity and obesity-related multiple diseases. Conclusion: Therefore, the identification and management of important contributory factors by identifying the regulation of adipocyte differentiation leading to a chronic condition like adipogenesis and insulin resistance resulting in obesity is an urgent requirement globally for human health.

Background: Alzheimer's disease (AD) is an irreversible multifaceted neurodegenerative disorder that gradually degrades neuronal cells. It is the most frequent cause of memory loss and dementia in elderly individuals worldwide. The extracellular deposition of beta amyloid (Aβ), intracellular neurofibrillary tangles (NFTs) retention, neuronal decline and neurotransmitter system derangement are the patho-physiological marker of this devastated disease Objective: In view of limited treatment option and their success rate, there is an urgent need to explore the vast array of proteomes for the management of AD. These proteins could be therapeutically targeted to prevent the progression of this disease. In the present review, we tried to uncover several proteins that could be exploited in AD therapeutics. Conclusion: Based on our article, we conclude that proteome based AD treatment needs more refinements and approaches to achieve the desired success rate.

Background: Bacteriocin have been tested as safe and effective alternative molecules over the currently used chemotherapeutic agents. Thus, being an important clinical significance, its screening and recovery methods along with its application are poorly described. Therefore, their screening, purification strategies and utilities must me extended. Thus, in this review, we, summarize potential application, various screening and purification methods used for recovery of bacteriocins. Methods: To complete this review, many reviews and previously published reports were studied. We, concentrated on review question and exclusion and inclusion criteria. The quality of content was evaluated by the quality the quality contents evaluation method. The standard method is used to describe the useful contents of available resources and appraised. Results: One hundred twenty research and review reports were used to complete this report. Sixty reports were used to make a collective information on screening and production of Bacteriocin Eighty two papers were used to explore the antimicrobial, therapeutic, diagnostic etc potentialities of bacteriocin in diverse field. The summarize form of data also presented in the form of tables and figures. This review describes the various methods and parameters that must be considered during the screening and purification methods. Moreover, the useful information is collected in regard represent it therapeutic potentialities in various fields for the welfare of human being. Conclusions: The conclusion of this review presented the significance of a fundamental framework for planning to understanding the basic requirement needed for fast, cost effective screening and purification of bacteriocins. The summered area of their utilities also helpful to extend the research field of bacteriocin. Thus, this report would be useful not only to scale up the screening and production strategies faster at economical rate, but also provides a platform to extend the research field of bacteriocin in many ways.

Background: Growing world population and continuous disease emergence have invited the development of more efficient new vaccines against a range of diseases. Conventional vaccines are being wildly used in the world but their production requires higher cost, more time and better infrastructure. Thus, the idea of plant-based edible vaccine technology has emerged and showed promising results with strong and effective protection against many diseases. Plants have been utilized since more than two decades as pharmaceuticals against many diseases. Methods: Plant-based technology has great potential to express genes and produce clinically important compounds in the desired tissue. Plant biotechnology has played important role in the production of pharmaceutical compounds like vaccines, antibodies, antigens, sub-units, growth hormones and enzymes by utilizing genetic modification. It has also been opened a new approach for developing an edible vaccine as an oral delivery. Results: Edible vaccines have been shown to induce both mucosal as well as systemic immunity. Currently, many pharmaceuticals proteins as an edible vaccine have been developed in different plant expression systems and evaluated against various life-threatening diseases and some of them have reached advanced phase of the clinical trial and exhibited promising results. Conclusion: In this review, we have discussed about the molecular pharming, edible vaccines, plant base technology and current status of developed edible vaccines in the different plant tissue expression system, mechanism of action and clinical applications with clinical trials stage, significance, requirements, advantage and disadvantage of edible vaccines.

Background: Drug repurposing is an innovative approach as it provides new indications for already approved and established drugs. Due to high failure rates and cost involved in traditional drug development procedures, many pharmaceutical companies are primarily focusing on drug repurposing strategy. In Alzheimer disease (AD), existing therapeutic agents only provide symptomatic benefits and does not play a role in disease modification, therefore, an alternative strategy of repurposing can be used to inhibit neurodegeneracy process and other pathological complications. This review discusses the beneficial effects of available licensed drug compounds which can be used as repurposed drugs for the treatment of AD. Moreover, it includes a brief overview of current treatment strategies, including therapies based on nanotechnology and their limitations. Methods: We attempted an organized scan of peer-reviewed research articles pertinent to licensed drugs that showed beneficial effects in Alzheimer's pathology. Our search includes in vitro studies, epidemiological data and clinical trials. In fact, we have collected, scrutinized, analyzed and discussed all the data that suggested the plausible application of repurposed drugs for the treatment of AD. Results: Cholinesterase inhibitors and N-methyl-D-Aspartate receptor antagonist are available options to improve the cognitive functions of Alzheimer's patients. These drugs only help in balancing disturbed level of neurotransmitters and are not helpful in disease modification. On the other hand, the nanotechnological based approach has promised to solve some challenges, but has certain limitations such as biocompatibility issues, therefore, it requires an extensive amount of research work. As our main emphasis was on repurposed drugs, we have performed an extensive review of articles to identify compounds that have been approved by the United States Food and Drug Administration for the treatment of diseases other than Alzheimer's but might have an impact on AD modification based on clinical evidences. Amyloid clearance, tau pathology and anti-inflammatory mechanisms are potential factors that are taken into consideration for disease modification. In addition, the role of bioinformatics and in silico drug repurposing strategy is crucial in the field of drug research, and plays a significant role in the identification of potential repurposed drugs. Thus, we have also mentioned several drug repurposing computational tools that are robust and can predict reliable results based on available gene expression data. Discussion: The major advantage of repurposing strategy is the identification of drug compounds with known mechanism of action, toxicology information and pharmacodynamics profiles; hence, less time is required for devising AD modification treatment. There are some issues as well with this method, which can be resolved by extending our research in this domain. Conclusion: AD is incurable, and there is an urgent need to find new treatments, as it is affecting the number of families and society overall. The drug repurposing approach is gaining attention in the pharmaceutical world, as it can substantially reduce the time and cost required to advance any treatment to the stage of clinical trials..

Background: The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- β-carboline alkaloid was investigated for both therapeutic and toxicological potential. Methods: The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. Results: The harmane-β-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. Conclusions: All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing.

Background: Antimicrobial resistance is quickly spreading and has become a major public health problem worldwide. If this issue is not resolved, it may cause a shift back to the pre-antibiotics era and infectious disease will again be a serious problem, especially in developing countries. Since the discovery of antibiotics, bacterial resistance has emerged, enabling certain bacteria to withstand antibiotic action. The emergence of antibiotic resistance is fueled by excessive and improper use of antimicrobial agents, especially in developing countries. For this reason, alternatives to or modifications of current treatment methods have been sought. The aim of this review is to highlight the possible synergies of various agents that can augment antibiotic activities. Methods: A structured literature search was conducted using only papers that have been published in PubMed with the focus on the agents that are likely to modulate antimicrobial resistance. In this review, data was retrieved from the literature regarding the possible synergies that exist between commercially available antimicrobial drugs with agents of interest. The papers included were summarized and analyzed, critiqued and compared for their contents using a conceptual frame-work. Results: In total, one hundred and twenty six papers were reviewed. The number of papers that dealt with the different topics included are as follows (): emergence of antimicrobial resistance (22), bioactive phyto-compounds (36) (phytobiologics, and phytochemicals), Antioxidants (40) (N-acetylcysteine, Ambroxol, Ascorbic acid, Glutathione and vitamin E), Peptide synergies (14) (Synthetic cationic α-helical AMPs, CopA3, Alafosfalin, PMAP-36, Phosphonopeptide L-norvalyl-L-1-aminoethylphosphonic acid and norcardicin-A), nano-antibiotics (10), drug-compound interactions (4).This review addressed the new strategies using the above compounds in the modulation of antimicrobial resistance to avoid issues related to resistance of bacteria to antibiotics. Conclusions: The findings of this review confirm that certain compounds can act in synergy with currently used antimicrobials to enhance the potential of antimicrobial agents and thus to reduce the emergence of antimicrobial resistance. Some of these synergies are already being used to enhance the potential of currently used antimicrobial agents. More studies need to be conducted to better understand the mechanism of action of such compounds, and based on the results, new compounds may be sought.

Background: Despite having extensive research, the apparent pathogenic mechanism of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDs) have not yet fully understood. The Heat Shock Protein 90 (HSP90), a ubiquitous molecular chaperone, found to have an important role in averting protein misfolding and aggregation through inhibition of apoptotic activity in neuro-inflammatory diseases. Various researchers have confirmed its role in maintaining aberrant neuronal protein's functional stability to a great capacity. It is also involved in regulating the activity of the heat shock factor-1 (HSF-1), a vital regulator of the heat shock response mechanism that cells employ to protect themselves against stress conditions. This quality makes the HSP90 an ideal candidate for novel inhibitory target for therapeutic modality in NDs. Methods: An extensive literature search was conducted for relevant studies on PubMed, ScienceDirect, Springer- Link etc. The articles were carefully read in their entirety to determine whether they contained information on the topic of interest. Additionally, the reference sections of these articles were searched manually to get more relevant and eligible studies. Results: We have taken an attempt to reveal how HSP90 play important roles with key neuronal proteins involved in supporting the AD and PD pathology. We have further on structure-function relationship of HSP90 to understand its efficacy as a new target in AD and PD by utilizing new generation of HSP90 inhibitors such as geldanamycin and its derivatives, 17-AAG, 17-DMAG, IPI-504, radicicol and its derivatives. HSP90 inhibition leads to suppress atypical neuronal activity by assisting in improving protein aggregation and its related toxicity. Further, the formation of neuronal aggregates is also influenced by HSP90 inhibitors and provides protection from toxicity of protein through HSF-1 activation and HSP70 induction in AD. Conclusion: HSP90 inhibition has emerged as a potential target in treating diverse array of diseases especially NDs. In spite of a large amount of research in this direction, the clear cut molecular mechanisms of HSPs associated with neuroprotection are still poorly elucidated and hence more focus is needed toward HSPs and its inhibitory mechanism. The development of HSP90 inhibitors that induce heat-shock response without cytotoxicity for treatment of NDs are still in its early stage. A panel of novel designed research and clinical trial studies are greatly needed to establish the therapeutic reliability and efficacy of HSPs in order to provide best cure for NDs.

Drug discovery and development is a time-consuming and resource-demanding process. Even with significant increases of the global R&D expenses, the pharmas' discovery engines have stalled. Therefore, any technologies that can improve the efficiency of the pipeline would be highly appreciated. Current state-of-the-art in silico techniques provide cost-effective and time-efficient approaches for lead discovery and optimization. These tools have been widely applied to the pipeline, from the very upstream of target identification and validation to the very downstream of ADMET (absorption, distribution, metabolism, elimination, and toxicity) and preclinical modeling. This special issue of Current Pharmaceutical Design, for which I am honored to be the Executive Guest Editor, focuses on utilizations of these in silico technologies in drug discovery and development. The authors have reviewed recent progress in lead identification and optimization, focusing primarily on the cutting-edge in silico approaches combined with in vitro and in vivo experimental validation. Additionally, this issue will bring significant contribution to the understanding of a variety of complex diseases (e.g., cancer) as well as those important therapeutic targets involved in these diseases. Therefore it is appropriate for multidisciplinary readers. Kinases are playing an important role in cancer development. Schnieders et al. focus on the mitogen activated protein (MAP) kinases due to their crucial functions in cellular signaling. The majority of currently known MAP kinase inhibitors target an ATP binding pocket that is highly conserved in the human kinome. Here the authors review the progress toward the development of non-ATP competitive inhibitors, and special emphasis is placed on computational methods. Topics include recent advances in X-ray crystallography theory that improve MAP kinase structures, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop, and inhibitors discovered by virtual screening. The impact of polarizable force fields such as AMOEBA is also discussed. In contrast to the non-ATP competitive agents, Wei and co-workers review a new type of kinase inhibitors, resorcylic acid lactones (RALs), which constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite their core scaffold distinct from current kinase inhibitors, RALs with a cis-enone moiety have shown irreversible yet selective inhibition on a subset of kinases. This review discusses their mechanism of action, synthetic strategies, and structure-activity relationships (SARs). It is anticipated that these RAL analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for cancer treatment. In addition to cancer, Acevedo and co-authors describe the application of free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics to the study of anti-HIV agents. They describe the early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. Furthermore, their ongoing work of optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted. Their FEP-guided optimization, experimental synthesis, and biological testing of lead compounds have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the above authors focus on one type of targets or methods for inhibitor discovery, Chen et al. provide a comprehensive review of using various structure-based drug design approaches for pharmaceutical development. The authors assess current progress and challenges in lead identification and optimization based on protein targets. The state-of-the-art techniques for protein modeling (e.g. active site prediction, target flexibility modeling, etc.), hit identification (e.g. docking, molecular dynamics, focused library design, etc.), and polypharmacology design are discussed. They also explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. While Chen et al. touch on targeting protein-protein interactions for inhibitor design, Bienstock specifically focuses on this topic. She presents the new challenges in the area and summarizes current computational and experimental methods available for protein-protein docking. This review also tabulates some examples of successful design of antagonists and small molecule inhibitors targeting protein-protein interactions. Several of these drugs are beginning to appear in the clinic. Along the same line, Morrow and Zhang put a spotlight on hot spot residue identification. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features and shown increasing predictive success. Here they give an overview of current in silico prediction techniques of hot spot residues with a case study on the TNF receptor-associated factor 6 (TRAF6) protein. The percentage of failures in late pharmaceutical development is increasing due to drug toxicities. In their review, Gleeson and colleagues discuss the challenges of building in silico models on toxicology endpoints and their practical use in decision making. Special focus is put on the data and methods used to generate in silico toxicology models. Their strengths and weaknesses are also discussed. They conclude that, while the in silico toxicology is a valuable tool for drug discovery, much still needs to be done to understand more about the biological mechanisms of toxicity and to generate more rapid in vitro models for compound screening. A successful, efficacious, and safe drug must have a balance of properties, including potency against intended targets, appropriate ADME properties, and acceptable safety profiles. To achieve this balance, Segall presents multi-parameter optimization (MPO) approaches to simultaneously optimize many factors. In particular, he illustrates how MPO can be applied to efficiently design and select high quality compounds. He also describes the range of methods that have been employed in drug discovery. Finally, Nussinov's laboratory provides a perspective for the orthosteric and allosteric drugs. The orthosteric drugs should bind strongly to the target, and this would allow high selectivity with a low dosage. By contrast, the binding of allosteric drugs to the protein surface perturbs the structure and this perturbation finally reaches the binding site. They provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development. This issue of Current Pharmaceutical Design includes a plethora of information across multiple disciplines. I wish to thank all the authors and co-authors for their commitments and outstanding work. Special thanks are also given to those anonymous reviewers who have contributed significantly by their constructive suggestions to the excellence of this issue.

Drug discovery and development is a time-consuming and resource-demanding process. Even with significant increases of the global R&D expenses, the pharmas' discovery engines have stalled. Therefore, any technologies that can improve the efficiency of the pipeline would be highly appreciated. Current state-of-the-art in silico techniques provide cost-effective and time-efficient approaches for lead discovery and optimization. These tools have been widely applied to the pipeline, from the very upstream of target identification and validation to the very downstream of ADMET (absorption, distribution, metabolism, elimination, and toxicity) and preclinical modeling. This special issue of Current Pharmaceutical Design, for which I am honored to be the Executive Guest Editor, focuses on utilizations of these in silico technologies in drug discovery and development. The authors have reviewed recent progress in lead identification and optimization, focusing primarily on the cutting-edge in silico approaches combined with in vitro and in vivo experimental validation. Additionally, this issue will bring significant contribution to the understanding of a variety of complex diseases (e.g., cancer) as well as those important therapeutic targets involved in these diseases. Therefore it is appropriate for multidisciplinary readers. Kinases are playing an important role in cancer development. Schnieders et al. focus on the mitogen activated protein (MAP) kinases due to their crucial functions in cellular signaling. The majority of currently known MAP kinase inhibitors target an ATP binding pocket that is highly conserved in the human kinome. Here the authors review the progress toward the development of non-ATP competitive inhibitors, and special emphasis is placed on computational methods. Topics include recent advances in X-ray crystallography theory that improve MAP kinase structures, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop, and inhibitors discovered by virtual screening. The impact of polarizable force fields such as AMOEBA is also discussed. In contrast to the non-ATP competitive agents, Wei and co-workers review a new type of kinase inhibitors, resorcylic acid lactones (RALs), which constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite their core scaffold distinct from current kinase inhibitors, RALs with a cis-enone moiety have shown irreversible yet selective inhibition on a subset of kinases. This review discusses their mechanism of action, synthetic strategies, and structure-activity relationships (SARs). It is anticipated that these RAL analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for cancer treatment. In addition to cancer, Acevedo and co-authors describe the application of free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics to the study of anti-HIV agents. They describe the early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. Furthermore, their ongoing work of optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted. Their FEP-guided optimization, experimental synthesis, and biological testing of lead compounds have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the above authors focus on one type of targets or methods for inhibitor discovery, Chen et al. provide a comprehensive review of using various structure-based drug design approaches for pharmaceutical development. The authors assess current progress and challenges in lead identification and optimization based on protein targets. The state-of-the-art techniques for protein modeling (e.g. active site prediction, target flexibility modeling, etc.), hit identification (e.g. docking, molecular dynamics, focused library design, etc.), and polypharmacology design are discussed. They also explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. While Chen et al. touch on targeting protein-protein interactions for inhibitor design, Bienstock specifically focuses on this topic. She presents the new challenges in the area and summarizes current computational and experimental methods available for protein-protein docking. This review also tabulates some examples of successful design of antagonists and small molecule inhibitors targeting protein-protein interactions. Several of these drugs are beginning to appear in the clinic. Along the same line, Morrow and Zhang put a spotlight on hot spot residue identification. Hot spot residues have unique and diverse energetic properties that make them challenging yet important targets in the modulation of protein-protein complexes. Design of therapeutic agents that interact with hot spot residues has proven to be a valid methodology in disrupting unwanted protein-protein interactions. Recent advances in computational approaches to predict hot spots have incorporated a myriad of features and shown increasing predictive success. Here they give an overview of current in silico prediction techniques of hot spot residues with a case study on the TNF receptor-associated factor 6 (TRAF6) protein. The percentage of failures in late pharmaceutical development is increasing due to drug toxicities. In their review, Gleeson and colleagues discuss the challenges of building in silico models on toxicology endpoints and their practical use in decision making. Special focus is put on the data and methods used to generate in silico toxicology models. Their strengths and weaknesses are also discussed. They conclude that, while the in silico toxicology is a valuable tool for drug discovery, much still needs to be done to understand more about the biological mechanisms of toxicity and to generate more rapid in vitro models for compound screening. A successful, efficacious, and safe drug must have a balance of properties, including potency against intended targets, appropriate ADME properties, and acceptable safety profiles. To achieve this balance, Segall presents multi-parameter optimization (MPO) approaches to simultaneously optimize many factors. In particular, he illustrates how MPO can be applied to efficiently design and select high quality compounds. He also describes the range of methods that have been employed in drug discovery. Finally, Nussinov's laboratory provides a perspective for the orthosteric and allosteric drugs. The orthosteric drugs should bind strongly to the target, and this would allow high selectivity with a low dosage. By contrast, the binding of allosteric drugs to the protein surface perturbs the structure and this perturbation finally reaches the binding site. They provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development. This issue of Current Pharmaceutical Design includes a plethora of information across multiple disciplines. I wish to thank all the authors and co-authors for their commitments and outstanding work. Special thanks are also given to those anonymous reviewers who have contributed significantly by their constructive suggestions to the excellence of this issue.

Due to their role in cellular signaling mitogen activated protein (MAP) kinases represent targets of pharmaceutical interest. However, the majority of known MAP kinase inhibitors compete with cellular ATP and target an ATP binding pocket that is highly conserved in the 500 plus representatives of the human protein kinase family. Here we review progress toward the development of non-ATP competitive MAP kinase inhibitors for the extracellular signal regulated kinases (ERK1/2), the c-jun N-terminal kinases (JNK1/2/3) and the p38 MAPKs (α, β, γ, and δ). Special emphasis is placed on the role of computational methods in the drug discovery process for MAP kinases. Topics include recent advances in X-ray crystallography theory that improve the MAP kinase structures essential to structurebased drug discovery, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop and inhibitors discovered by virtual screening. The impact of an advanced polarizable force field such as AMOEBA used in conjunction with sophisticated kinetic and thermodynamic simulation methods is also discussed.

Due to their role in cellular signaling mitogen activated protein (MAP) kinases represent targets of pharmaceutical interest. However, the majority of known MAP kinase inhibitors compete with cellular ATP and target an ATP binding pocket that is highly conserved in the 500 plus representatives of the human protein kinase family. Here we review progress toward the development of non-ATP competitive MAP kinase inhibitors for the extracellular signal regulated kinases (ERK1/2), the c-jun N-terminal kinases (JNK1/2/3) and the p38 MAPKs (α, β, γ, and δ). Special emphasis is placed on the role of computational methods in the drug discovery process for MAP kinases. Topics include recent advances in X-ray crystallography theory that improve the MAP kinase structures essential to structurebased drug discovery, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop and inhibitors discovered by virtual screening. The impact of an advanced polarizable force field such as AMOEBA used in conjunction with sophisticated kinetic and thermodynamic simulation methods is also discussed.

Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cisenone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.

Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cisenone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting proteinligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/ optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.