Abstract:
: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.
journal_name
Curr Pharm Desjournal_title
Current pharmaceutical designauthors
Acevedo O,Ambrose Z,Flaherty PT,Aamer H,Jain P,Sambasivarao SVdoi
10.2174/138161212799436421subject
Has Abstractpub_date
2012-01-01 00:00:00pages
1199-216issue
9eissn
1381-6128issn
1873-4286pii
CPD-EPUB-20120203-003journal_volume
18pub_type
杂志文章,评审abstract::The so-called hygiene hypothesis is, at least in part, accountable for the increase in allergic diseases in the developed countries. Although there is support for one of its primary predictions that host-microbe interactions in early life have longterm effects on the development of disease across populations, the theo...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161212800166031
更新日期:2012-01-01 00:00:00
abstract::The mechanisms and factors causing or influencing degenerative diseases require tailor-made solutions. Natural polysaccharides are among the most versatile building units of the novel drug delivery systems. Their properties can be easily tailored to specific needs because they depend not only on the first-order struct...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161212800492831
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abstract:BACKGROUND:The development of appropriate pharmaceutical formulations for routine neonatal practice is challenging because of the developmental characteristics and the need for it to be specifically ageappropriate. This has led to wide use of extemporaneous formulations, which lack standardized procedures that can resu...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612823666170926122613
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abstract::Over the last two decades, SPECT (single photon emission computed tomography) and especially PET (positron emission tomography) have proven increasingly effective imaging modalities in the study of human psychopharmacology. Abusing populations can be studied at multiple times after abstinence begins, to give informati...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161205774424717
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:A mobile health application is an exciting, fast-paced domain that is likely to improve prenatal care. METHODS:In this narrative review, we summarise the use of mobile health applications in this setting with a special emphasis on both the benefits of remote monitoring devices and the potential pitfalls of ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612825666190320140659
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abstract::Acute kidney injury (AKI) is relatively common in patients undergoing transcatheter aortic valve implantation (TAVI) and has been associated with increased mortality and worse outcomes. The administration of iodinated contrast media in an elderly population with increased rates of chronic kidney injury and heart failu...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612822666151208120522
更新日期:2016-01-01 00:00:00
abstract::Development of effective drug delivery systems is important for medicine and healthcare. Polymer particulates (micro- and nanoparticles) have opened new opportunities in the field of drug delivery by overcoming various limitations of conventional delivery methods. The properties of polymeric particles can be readily t...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612822666160217125734
更新日期:2016-01-01 00:00:00
abstract::Protein palmitoylation is a fundamental and reversible post-translational lipid modification that involves a series of biological processes. Although a large number of experimental studies have explored the molecular mechanism behind the palmitoylation process, the computational methods has attracted much attention fo...
journal_title:Current pharmaceutical design
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doi:10.2174/1381612826666201112142826
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abstract::Tumor metastasis is an important prognostic factor regarding long-term survival rate of cancer patients. At present, no imaging modality or technique is ideal for diagnosis of metastases. Molecular imaging has provided a fantastic tool for tumor metastases imaging. Based on the current medical imaging tools such as ma...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612821666151027153943
更新日期:2015-01-01 00:00:00
abstract::The organ shortage for kidney transplantation remains a challenging issue worldwide. Incompatibility between donor-recipient pairs, commonly occurring among transplant candidates who were sensitized from prior antigen exposure, serves as a significant barrier to kidney transplantation. In efforts to overcome this obst...
journal_title:Current pharmaceutical design
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abstract::Fibrate derivatives have a 40-year history in the management of dyslipidemia. Although this class of drugs is generally well tolerated, several safety issues have arisen from their use. In the present article we review the literature describing side effects associated with the use of fibrates except for those that are...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161208783885362
更新日期:2008-01-01 00:00:00
abstract::The vasoconstrictive and antidiuretic physiologic properties of vasopressin (antidiuretic hormone) have long been known. Until recently however, vasopressin was mostly used for diabetes insipidus and noctournal enuresis. This review summarizes the growing body of evidence regarding the perioperative use of vasopressin...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161212803832326
更新日期:2012-01-01 00:00:00
abstract:BACKGROUND:Absorption windows in particular segments of the small intestine can contribute to the development of orally administered drug formulations and can limit the bioavailability of released compounds. OBJECTIVE:The aim of this study was to evaluate use of wireless capsule enteroscopy regarding the disintegratio...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/1381612822666161201145247
更新日期:2017-01-01 00:00:00
abstract::New biopharmaceutical molecules, potentially able to provide more personalized and effective treatments, are being identified through the advent of advanced synthetic biology strategies, sophisticated chemical synthesis approaches, and new analytical methods to assess biological potency. However, translation of many o...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612822666151216151420
更新日期:2016-01-01 00:00:00
abstract::In the present review, associations between traditional vascular risk factors (VRFs) and carotid intimamedial thickness progression (C-IMTp) as well as the effects of therapies for VRFs control on C-IMTp were appraised to infer causality between each VRF and C-IMTp. Cohort studies indicate that smoking, binge drinking...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612825666191213120339
更新日期:2020-01-01 00:00:00
abstract::Most heterosexual women want to reduce the risk of acquiring a sexually transmitted infection; many also want to control their fertility. Several chemical agents have been proposed to dramatically slow the spread of HIV infections. Ideally, vaginal microbicides, with or without contraceptive properties, should be safe...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161205774580705
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased inc...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612824666181009105305
更新日期:2018-01-01 00:00:00
abstract::Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can self-renew indefinitely, while maintaining the capacity to differentiate into useful somatic cell types, including cardiomyocytes. As such, these stem cell types represent an essentially inexhaustible source of committed human cardiomyo...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161209788923804
更新日期:2009-01-01 00:00:00
abstract::Drug development for neurodegenerative diseases such as Alzheimer's disease (AD) is a challenge, not only due to the cellular molecular mechanisms involved, but also because of the inherent difficulty of most molecules to cross the blood-brain-barrier (BBB). A promising approach to overcome these drawbacks is developi...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612821666150130120358
更新日期:2015-01-01 00:00:00
abstract::In drug development, in vitro human model systems are absolutely essential prior to the clinical trials, considering the increasing number of chemical compounds in need of testing, and, keeping in mind that animals cannot predict all the adverse human health effects and reactions, due to the species-specific differenc...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
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更新日期:2017-01-01 00:00:00
abstract::Epicardial adipose tissue is not only a specific adipose tissue depot but also an active endocrine organ producing numerous substances with an important role in the development of obesity-related heart diseases. It is located between myocardium and visceral pericardium and consists predominantly of adipocytes, immunoc...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612824666180110102125
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abstract::Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pat...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612043383124
更新日期:2004-01-01 00:00:00
abstract::There is growing evidence for the involvement of glutamatergic abnormalities in schizophrenia. Uncompetitive NMDA receptor (NMDAR) antagonists induce effects closely resembling both the positive and negative symptoms of schizophrenia; candidate risk genes for schizophrenia converge on the NMDAR expressing synapse; and...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161209788957438
更新日期:2009-01-01 00:00:00
abstract::Gene therapy, currently, represents one of the new therapies that have emerged for the treatment of different diseases. Between the different approaches that can be chosen concerning this therapy, gene delivery with non-viral systems has focused the attention during the past decades, because of the reduced toxicity co...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612821666150901100037
更新日期:2015-01-01 00:00:00
abstract::The pharmacophore concept is central to the rational drug design and discovery process. Traditionally, a pharmacophore is defined as a specific three-dimensional (3D) arrangement of chemical functional groups found in active molecules, which are characteristic of a certain pharmacological class of compounds. Herein, b...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612013397834
更新日期:2001-05-01 00:00:00
abstract::Recent advances in DNA sequencing has made it possible to accurately decipher the entire genetic complement of a probiotic bacterium. Increases in sequencing capabilities have been enhanced through improved computer software that can annotate, or identify, the majority of genes encoded by the sequence. The availabilit...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/1381612053382377
更新日期:2005-01-01 00:00:00
abstract::Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze CO(2) hydration to bicarbonate and protons. Five genetically distinct classes are known, which represent an excellent example of convergent evolution. Inhibition of α-CAs from vertebrates, including humans, with sulfonamides was exploited clinical...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161210793429797
更新日期:2010-01-01 00:00:00
abstract::Subjects affected by ischemic heart disease with non-obstructive coronary arteries constitute a population that has received increasing attention over the past two decades. Since the first studies with coronary angiography, female patients have been reported to have non-obstructive coronary artery disease more frequen...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/1381612826666201012163845
更新日期:2020-10-12 00:00:00
abstract::In recent years, nanosuspensions have been accepted as a valuable drug delivery system for poorly water-soluble drugs. Topdown and bottom-up technologies are the two main approaches for generating nanosuspensions. Several products manufactured by the top-down technologies have been successfully commercialized demonstr...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
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更新日期:2014-01-01 00:00:00
abstract::Diterpenes present complex structure and due to their unique carbon skeleton and interesting biological activities, have been the focus of continuous studies for the development of new anticancer agents. Phorbol esters have been known for their activity against skin malignancies since ancient times. Taxol was first st...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612825666190111143648
更新日期:2018-01-01 00:00:00