Abstract
Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes related to age. In this sense, the so-called senoylitic compounds are a class of drugs that selectively eliminates senescent cells (SCs) and that could be used in order to delay such adverse outcomes. Interestingly, the first senolytic drug (navitoclax) was discovered by using chemoinformatic and network analyses. Thus, in the present study, we searched for novel senolytic compounds through the use of chemoinformatic tools (fingerprinting and network pharmacology) over different chemical databases (InflamNat and BIOFACQUIM) coming from natural products (NPs) that have proven to be quite remarkable for drug development. As a result of screening, we obtained three molecules (hinokitiol, preussomerin C, and tanshinone I) that could be considered senolytic compound candidates since they share similarities in structure with senolytic leads (tunicamycin, ginsenoside Rb1, ABT 737, rapamycin, navitoclax, timosaponin A-III, digoxin, roxithromycin, and azithromycin) and targets involved in senescence pathways with potential use in the treatment of age-related diseases.
Highlights
During aging, immune clearance defects lead to the accumulation of senescent cells, which are thought to limit tissue by releasing the so-called senescence-associated secretory phenotype (SASP), creating a mild but chronic proinflammatory microenvironment that may impair the normal function of surrounding tissue [1]
We found two main clusters of senolytic compounds according to their 1-D and 2-D molecular descriptors focused on molecular.flexibility, H.Donors, Veber..violations, Muegge..violations, Lipinski..violations, nviolations, H.Acceptors, polar.surface.area, electronegative.atoms, sp3.atoms, molweight, natoms, total.surface.area, rotatable.bonds, Egan..violations, and
Our results show that the compounds hinokitiol, preussomerin C, and tanshinone-I
Summary
Cellular senescence is a biological condition that involves significant changes in gene expression and the loss of proliferative potential. During aging, immune clearance defects lead to the accumulation of senescent cells, which are thought to limit tissue by releasing the so-called senescence-associated secretory phenotype (SASP), creating a mild but chronic proinflammatory microenvironment that may impair the normal function of surrounding tissue [1]. Such an environment has been associated with several diseases such as cancer, cardiovascular disease, obesity, type 2 diabetes, sarcopenia, pulmonary fibrosis, osteoarthritis, atherosclerosis, and neurological disorders [1]. Senescent cells have upregulated pro-survival/antiapoptotic mechanisms such as the PI3K/Akt and
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