1,721,245 research outputs found
Building a pharmacophore model for antitubercular compounds acting as inhibitors of mycoli acid biosynthesis
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Pharmacophore-based improvement of affinity toward a1-adrenergic receptors
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Recent advances in the rational design and development of LIM kinase inhibitors are not enough to enter clinical trials
No full textLIM kinases are involved in various pathophysiological processes that depend on actin organization.
Alteration of microtubule dynamics by LIMK dysregulation is in fact related to tumor progression and
metastasis, viral infection, and ocular diseases, such as glaucoma. As a consequence, many efforts have
been done in recent years to rationally design small molecules able to inhibit LIMK activity selectively,
without affecting other kinases. As a result, compounds optimized in terms of binding affinity and
pharmacokinetic parameters have been discovered, that however failed to access clinical trials. In this
review, a comprehensive survey of recent LIMK inhibitors is reported, together with SAR considerations
and optimization processes
LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators
No full textThe LIM kinases 1 and 2 (LIMK1 and LIMK2) are dual specificity (serine/threonine and tyrosine) kinases. Although they show significant structural similarity, LIMK1 and LIMK2 show different expression, subcellular localization, and functions. They are involved in many cellular functions, such as migration, cycle, and neuronal differentiation and also have a role in pathological
processes, such as cancer cell invasion and metastatis, as well as in neurodevelopmental disorders (namely, the William’s syndrome). LIM kinases have a relevant number of known partners that are able to induce or limit the ability of LIMK1 and LIMK2 to phosphorylate and inactivate their major substrate, cofilin. On the contrary, only a limited number of small molecules that interact with the two proteins to modulate their kinase activity have been identified. In this review, the most important
partners of LIM kinases and their modulating activity toward LIMKs are described. The small compounds identified as LIMK1 and LIMK2 modulators are also reported, as well as their role as possible therapeutic agents for LIMK-induced diseases
HIV-1 proteins join the family of LIM kinase partners. New roads open up for HIV-1 treatment
No full textLIM kinases (LIMK) exert their functions by recruiting many macromolecular partners that could contribute to modulate LIMK activity in a positive or negative manner. In addition to proteins that interact with LIMK in human or animal cells and tissues, recent data show that LIMK activity is also influenced by HIV-1 viral proteins. These results suggest new strategies for the treatment of HIV-1 infection, based on the inhibition of LIMK-mediated cofilin inactivation and consequent actin depolymerization. Further efforts are however required to unravel the mechanism by which the virus interferes with LIMK activity and with the right balance of actin remodeling
Recent research results have converted gp120 binders to a therapeutic option for the treatment of HIV-1 infection. A medicinal chemistry point of view
No full textCurrent therapeutic armamentarium for treatment of HIV-1 infection is based on the use of highly active
antiretroviral therapy that, unfortunately, does not act as a curative remedy. Moreover, duration of the
therapy often results in lack of compliance with the consequent emergence of multidrug resistance. Finally,
drug toxicity issues also arise during treatments. In the attempt to achieve a curative effect, in addition to
invest substantial resources in finding new anti-HIV-1 agents and in optimizing antiviral lead compounds
and drugs currently available, additional efforts should be done to deplete viral reservoir located within
host CD4þ T cells. Gp120 binders represent a class of compounds able to affect the interactions between
viral envelope proteins and host CD4, thus avoiding virus-to-cell attachment and fusion, and the consequent
viral entry into host cells. This review summarizes the efforts done in the last five years to design
new gp120 binders, that finally culminated in the approval of fostemsavir as an anti-HIV-1 drug
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