In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies

Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod

Distribution of alien species along sand dune plant communities zonation

Background and purpose: For a fairly long period, Velika plaža in Ulcinj, Montenegro has been considered to be one of the best-preserved sites with psammophilous vegetation along the Adriatic coast. In recent years, however, this area has been significantly transformed as a result of various human disturbances (e.g., a non-sustainable approach to touristic development, illegal dumping, sand exploitation etc.), and has become prone to alien plant invasions. We made a transect survey to assess the presence of alien species in the psammophilous communities.Materials and methods: In order to make a survey of the present state of plant life on Velika plaža, its floristic composition and zonation of plant communities, 20 transects were set perpendicular to the coast, regularly every 500 m. Quadrats (2 x 2 m) were laid contiguously in the form of a belt transect starting from the area with the first colonizing plants towards the end of the sand dune system with forest vegetation. This resulted in a matrix of 1124 plots and 196 species (15 alien and 181 native), on which multivariate analysis was performed.Results: Nine plant communities were detected, arranged in zonation from sea to inland. All of them were characterised by the presence of alien species. The least affected was the plant community dominated by Cladium mariscus, while the most affected ones were dominated by Scirpoides holoschoenus and Tripidium ravennae. Psammophilous vegetation is less affected by alien species than wetland communities. Foredunes are dominated by Xanthium orientale ssp. italicum, while Oenothera species are predominant on stable dunes.Conclusions: Sand dunes are a highly invaded ecosystem, with changed plant communities, so conservation measures should be considered.</p

Medicinska hemija inhibitora histon deacetilaza

Today, we are witnessing an explosion of scientific concepts in cancer chemotherapy. It has been considered for a long time that genetic instability in cancer should be treated with drugs that directly damage the DNA. Understanding the molecular basis of malignant diseases shed light on studying phenotypic plasticity. In the era of epigenetics, many efforts are being made to alter the aberrant homeostasis in cancer without modifying the DNA sequence. One such strategy is modulation of the lysine acetylome in human cancers. To remove the acetyl group from the histones, cells use the enzymes that are called histone deacetylases (HDACs). The disturbed equilibrium between acetylation and deacetylation on lysine residues of histones can be manipulated with histone deacetylase inhibitors (HDACi). Throughout the review, an effort will be made to present the mechanistic basis of targeting the HDAC isoforms, discovered selective HDAC inhibitors, and their therapeutical implications and expectations in modern drug discovery.Savremena hemoterapija kancera se bazira na velikom broju različitih naučnih pristupa. Dugo se smatralo da bi genetsku nestabilnost u kancerskim oboljenjima trebalo lečiti agensima koji direktno oštećuju DNK. Razumevanje molekularnih osnova malignih oboljenja rasvetlilo je značaj fenotipske plastičnosti. U eri epigenetike, učinjeni su mnogi napori da se izmeni aberantna homeostaza u kancerskom oboljenju bez modifikovanja sekvence DNK. Jedna od takvih strategija je modulacija lizinskog acetiloma u humanim kancerima. Da bi se acetil grupa uklonila sa histona, ćelije koriste enzime histon deacetilaze. Poremećena ravnoteža acetilacije i deacetilacije na lizinskim ostacima histona može biti regulisana inhibitorima histon deacetilaza. Kroz ovaj pregledni rad, biće prikazani mehanizmi inhibicije izoformi histon deacetilaza, različiti inhibitori histon deacetilaza, kao i njihove terapijske primene i očekivanja u modernom razvoju lekova

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies

Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors

Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity and selectivity are defined as: surface recognition group (CAP group), aliphatic or aromatic linker and zinc-binding group (ZBG). Herein, we describe a comprehensive protocol for the computational fragment search of novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase 6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl piperazine was employed to synthesize novel HDAC inhibitors with small structural perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. References 1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas, The Oncologist, 2021, 26(3), 184 e366. 2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5), 1800083. Acknowledgments The authors acknowledge a Ministry of Education, Science and Technological Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022- 14/200161).8th Conference of Young Chemists of Serbia 29th October 2022 University of Belgrade, Faculty of Chemistry Book of Abstracts M32 DRuzic Abstracts_8 CYCS BGD 202

Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer

Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors

Cryptosporidium Infection in Goats in Serbia

Cryptosporidiosis is an anthropozoonosis caused by coccidia of the family Cryptoporididae, whish may cause a serious health problem for kids in the first weeks of life. In our paper we presented results of examination of goat cryptosporidiosis in Serbia. In period 2016-2019 we examined 197 goat herds. Total of 1576 faecal smears were examined by Sheather’s sugar floatation technique and modified Ziehl–Neelsen staining technique. Cryptosporidiosis were found at 119 herds. Kids between five and twenty-one days old are the most susceptible. The morbidity varies from 75–100% and the mortality from 45-50%. Some animals do not develop into chronic cases and become carriers. After infection, animals either resist the organism, develop a mild infection that is self limiting, or soon sicken and die. Based on the performed research, we have established a significant role of cryptosporidiosis in the development of neonatal enteropathies of kids

Structure-Based Design of Selective Histone Deacetylase 6 Zinc Binding Groups

The binding site of the second catalytic domain of human histone deacetylase 6 (HDAC6 CDII) has structural features that differ from the other human orthologues, being also mainly responsible for the overall enzymatic activity of this isoform. Aiming to identify new fragments as a possible novel selective zinc binding group (ZBG) for HDAC6 CDII, two fragment libraries were designed: one library consisting of known chelators and a second one using the fragments of the ZINC15 database. The most promising fragments identified in a structure-based virtual screening of designed libraries were further evaluated through molecular docking and molecular dynamics simulations. An interesting benzimidazole fragment was selected from the in silico studies and presented as potential zing binding group for the development of novel HDAC6 selective inhibitors.This is peer-reviewed version of the following article:Alves Avelar, L. A.; Ruzic, D.; Djokovic, N.; Kurz, T.; Nikolic, K. Structure-Based Design of Selective Histone Deacetylase 6 Zinc Binding Groups. J. Biomol. Struct. Dyn. 2020, 38 (11), 3166–3177. [https://doi.org/10.1080/07391102.2019.1652687

Protosan in flocks of small ruminants in Belgrade area during 2020

During our research we examined flocks of small ruminant originated from 23 villages from city districts Mladenovac, Lazarevac, Obrenovac, Grocka, Zemun, Surčin, Palilula, Vozdovac and Zvezdara. In more than 80 percent of the herds, sheep and goats were breed together at same pasture. Using standard coprological methods we examined 273 faecal samples from 41 herds. Determination of parasites we performed by morphological characteristics. Molecular detection of Cryptosporidium sp. and Giardia sp. we not performed. Coccidiosis was found at 27 herds. We usally occured mixed infection with 2-3 coccidia species. At sheep most abundant coccidia were E faurei, followed by E.ovinoidalis, E. pallida and E.ahsata. At goats most abundant species were E.arlongy, folwed by E.nina-kohl-yakimovae, E. hirci and E. caprina. Clinical signs of disease were present only at young animals but oocysts were found at both, adult ant young animals. Cryptosporidium spp. was found at 19 herds Clinical signs of cryptosporidiosis were established only at young animals. They had moderate morbidity and mortality rate. Infection with Giardia duodenalis was found only at 2 herds. Giardia-infected animals generally had no clinical symptoms