Computational Approaches: Drug Discovery and Design in Medicinal Chemistry and Bioinformatics

This book is a collection of original research articles in the field of computer-aided drug design. It reports the use of current and validated computational approaches applied to drug discovery as well as the development of new computational tools to identify new and more potent drugs

Design, synthesis and biological evaluation of novel thiadiazoline-thiazolone hybrids as kinase inhibitors.

Masters Degree. University of KwaZulu-Natal, Durban. 2017Cancer is a leading cause of death globally, and it was responsible for 8.8 million deaths in 2015. It is predicted that there will be 22 million new cancer cases by 2030 worldwide. Approximately, 70% of deaths from cancer occur in low- and middle-income countries. Furthermore, breast cancer is the second most common cancer among South African women and is reported to affect 1 in every 26 women. The social and economic burdens associated with cancers are severe at national and international levels hence, there is an urgent need for the development of more effective cancer therapeutics. To accomplish this aspect, in this study, thiadiazole-thiazolone (TDT) hybrids were developed as dual inhibitors of cyclindependent kinase (CDK) and kinesin spindle protein (KSP), respectively. Twenty-two novel TDT hybrid compounds (8a-v) were synthesized using multistep organic synthesis and were characterized using thin layer chromatography (TLC), infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (1H and 13C NMR), and high-resolution mass spectrometry (HR-MS). All the compounds (8a-v) were screened for their potential in vitro inhibition of validated anticancer drug targets (CDK, Abl and KSP) and cancer cell lines (MCF-7 and K562). Results obtained from these evaluations suggested that the synthesized compounds were potent inhibitors of CDK and KSP thus confirming the dual mode of action. Amongst, 8h was identified as the most potent compound with an IC50 value of 3.1 µM against CDK2 enzyme and exhibited good cytotoxicity (GI50 = 6.25 µM) against the tested cancer cell lines (MCF-7 and K-562). A brief structure-activity relationship (SAR) analysis indicated that 2- chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to the inhibition of both of the anticancer drug targets (CDK and KSP). An in silico molecular docking study using the crystal structures of the target enzymes (CDK-2 and KSP) further supported the SAR and extrapolated the importance of crucial molecular interactions in influencing the enzyme inhibitory activitie

Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances II

This Special Issue, comprising five articles, describes the synthetic methodologies and biological activity of different classes of bioactive marine metabolites and analogs crucial to favor pharmacological applications of these molecules

Structural studies, design, identification and biological evaluation of bioactive compounds settore

2014 - 2015Computational methodologies in combination with experimental biological assay represent fundamental key tools in the drug discovery process. The study of ligand-macromolecule interactions has a crucial role for the design, the identification and the development of new chemical platforms as anti-inflammatory and anti-cancer agents. In this project, different aspects of interaction and recognition processes between ligand and targets, and stereostructure assignment of natural compounds has been studied through different in silico approaches with the determination of their biological activities, which allow to corroborate the predicted results... [edited by author]XIV n.s

Women in Bioorganic Chemistry

Issues relating to the gender schism and its effect on the career advancement of women in the Academy, especially in the field of STEM disciplines, deserve our attention and the efforts of all the scientific community to mitigate the gender gap. In order to embrace gender equality, recognize the career progression of women, and to celebrate the achievements of women in the field of bioorganic chemistry, we present contributions both from highly renowned female scientists and young female researchers who are in the early stages of their careers. This Special Issue includes fifteen manuscripts, including eleven high-quality research articles and four comprehensive review articles in the area of bioorganic chemistry, published from mid-2020 to early 2022. The scope of this Special Issue covers a wide range of topics at the organic chemistry–biology interface, including the synthesis and derivatization of natural compounds and their analogues, and the investigation of their biological activities in the human health field (for instance as antitumorals, antioxidants and antimicrobial agents), as well as their possible application in the crop protection field as agrochemicals. An example of nanoparticle-based biomaterial is also included. The techniques employed, besides organic synthesis, are in silico studies (docking procedures and molecular modeling), FT-IR spectroscopy, laser diffraction, PET, fluorescence, STD-NMR studies, enzymatic evaluation, experiments on cell lines and in vivo studies on mice

In Silico Strategies for Prospective Drug Repositionings

The discovery of new drugs is one of pharmaceutical research's most exciting and challenging tasks. Unfortunately, the conventional drug discovery procedure is chronophagous and seldom successful; furthermore, new drugs are needed to address our clinical challenges (e.g., new antibiotics, new anticancer drugs, new antivirals).Within this framework, drug repositioning—finding new pharmacodynamic properties for already approved drugs—becomes a worthy drug discovery strategy.Recent drug discovery techniques combine traditional tools with in silico strategies to identify previously unaccounted properties for drugs already in use. Indeed, big data exploration techniques capitalize on the ever-growing knowledge of drugs' structural and physicochemical properties, drug–target and drug–drug interactions, advances in human biochemistry, and the latest molecular and cellular biology discoveries.Following this new and exciting trend, this book is a collection of papers introducing innovative computational methods to identify potential candidates for drug repositioning. Thus, the papers in the Special Issue In Silico Strategies for Prospective Drug Repositionings introduce a wide array of in silico strategies such as complex network analysis, big data, machine learning, molecular docking, molecular dynamics simulation, and QSAR; these strategies target diverse diseases and medical conditions: COVID-19 and post-COVID-19 pulmonary fibrosis, non-small lung cancer, multiple sclerosis, toxoplasmosis, psychiatric disorders, or skin conditions

Non-covalent interactions in organotin(IV) derivatives of 5,7-ditertbutyl- and 5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine as recognition motifs in crystalline self- assembly and their in vitro antistaphylococcal activity

Non-covalent interactions are known to play a key role in biological compounds due to their stabilization of the tertiary and quaternary structure of proteins [1]. Ligands similar to purine rings, such as triazolo pyrimidine ones, are very versatile in their interactions with metals and can act as model systems for natural bio-inorganic compounds [2]. A considerable series (twelve novel compounds are reported) of 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) and 5,7-diphenyl- 1,2,4-triazolo[1,5-a]pyrimidine (dptp) were synthesized and investigated by FT-IR and 119Sn M\uf6ssbauer in the solid state and by 1H and 13C NMR spectroscopy, in solution [3]. The X-ray crystal and molecular structures of Et2SnCl2(dbtp)2 and Ph2SnCl2(EtOH)2(dptp)2 were described, in this latter pyrimidine molecules are not directly bound to the metal center but strictly H-bonded, through N(3), to the -OH group of the ethanol moieties. The network of hydrogen bonding and aromatic interactions involving pyrimidine and phenyl rings in both complexes drives their self-assembly. Noncovalent interactions involving aromatic rings are key processes in both chemical and biological recognition, contributing to overall complex stability and forming recognition motifs. It is noteworthy that in Ph2SnCl2(EtOH)2(dptp)2 \u3c0\u2013\u3c0 stacking interactions between pairs of antiparallel triazolopyrimidine rings mimick basepair interactions physiologically occurring in DNA (Fig.1). M\uf6ssbauer spectra suggest for Et2SnCl2(dbtp)2 a distorted octahedral structure, with C-Sn-C bond angles lower than 180\ub0. The estimated angle for Et2SnCl2(dbtp)2 is virtually identical to that determined by X-ray diffraction. Ph2SnCl2(EtOH)2(dptp)2 is characterized by an essentially linear C-Sn-C fragment according to the X-ray all-trans structure. The compounds were screened for their in vitro antibacterial activity on a group of reference staphylococcal strains susceptible or resistant to methicillin and against two reference Gramnegative pathogens [4] . We tested the biological activity of all the specimen against a group of staphylococcal reference strains (S. aureus ATCC 25923, S. aureus ATCC 29213, methicillin resistant S. aureus 43866 and S. epidermidis RP62A) along with Gram-negative pathogens (P. aeruginosa ATCC9027 and E. coli ATCC25922). Ph2SnCl2(EtOH)2(dptp)2 showed good antibacterial activity with a MIC value of 5 \u3bcg mL-1 against S. aureus ATCC29213 and also resulted active against methicillin resistant S. epidermidis RP62A

Design and synthesis of novel compounds interacting with modulatory cysteines of MGL

N-arachidonoyletanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the most representative members of a class of endogenous ligands named endocannabinoid, which are able to activate cannabinoids receptors. The endocannabinoid neuromodulation plays important roles in various aspects of neural functions including learning and memory, anxiety, depression, appetite and feeding behavior, nociception, neuroprotection and movement control. Since 2-AG has been considered the true on-demand released endocannabinoid ligand for CB1 receptor, a promising way to explore and promote its therapeutic potential could be the selective inhibition of the monoacylglycerol lipase (MGL), the enzyme responsible of 2-AG degradation. Three critical residues of cysteine have been identified as regulatory gates for the activity of the enzyme: Cys242, within the active site close to the catalytic triad, Cys201 and Cys208 located on the lid domain, a flexible solvent-exposed region that regulate the access of the substrate to the active site. Cys201 and Cys208 have been recently shown to be redox switches that regulate the activity of MGL by undergoing oxidation after oxidative stimulus induced by hydrogen peroxide. Despite the potential of MGL as target for 2-AG signaling modulation, few potent and selective MGL inhibitors are available until now. Recently two class of partially-reversible MGL inhibitors has been reported: one is populated by covalent disulfide-bond forming compounds such as isothiazol-3(2H)-one (ITZ) and benzo[d]isothiazol-3(2H)-one (BTZ) derivatives, the second one is populated by triterpenes such as euphol and pristimerin. Both these classes of compounds interact with critical residues Cys201 and Cys208 of MGL thus preserving the catalytic activity of the enzyme. The modulation of MGL activity by interaction with these critical cysteine residues is a crucial point to fine tune the 2-AG signaling avoiding behavioral side-effects associated to the total disruption of the catalytic activity of MGL exerted by inhibitors addressing the catalytic site The research work reported in this PhD dissertation has been focused on the exploration of the structure-activity relationships (SAR) around the BTZ warhead in order to explore the pharmacophoric space around the targeted cysteines of MGL. The structure of the driver portion of compounds sharing an identical warhead has been broadly changed. I investigated the effect of substituent groups with different steric demand and electronic inductive effects on the nitrogen atom and the substituents on the phenyl ring of BTZ. I performed the design and the synthesis of several compounds, applying different synthetic strategies. The inhibitory potency of synthesized BTZs on MGL and was evaluated and SAR of this class were described. We identified promising compounds with inhibitory potency on MGL in the low nanomolar range. Moreover, the lead compound emerged from this screening was subjected to mechanistic studies that revealed a behavior similar to that of hydrogen peroxide in inactivating MGL supporting the theory that BTZs mimic the effect of an endogenous oxidation stimulus. To further elucidate the role of critical Cys201 and Cys208 in MGL activity, site-directed mutagenesis studies were performed identifying both cysteines as possible counterpart in the interaction with BTZs. Moreover, in order to evaluate the stability and reactivity of these compounds towards biological thiols we investigated, trough analytical methods the effect of substituent groups with different steric hindrance and electronic effects on the sulfenamidic reactive core of BTZ. I investigated by means of NMR experiments the reactivity of selected BTZs with a model biological thiol, N-acetyl cysteine (NAC). These studies allowed us to define a structure-reactivity relationship landscape that further validated our biological results. To increse the knolewdge in the field of the terpene-based inhibitors of MGL, I synthesized 3 new compounds starting form commercially available celastrol: these scaffold modifications led to less active compounds than reference compound pristimerin thus discouraging the development of triperpene-based MGL inhibitors. Fibroblast growth factor-2 (FGF2) is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. FGF2 stimulates the growth and development of new blood vessels (angiogenesis) that contribute to the pathogenesis of several diseases (i.e. cancer, atherosclerosis), normal wound healing and tissue development. FGF2 exerts its activity on endothelial cells by interacting with high affinity tyrosine-kinase FGF receptors (FGFRs) and low affinity heparan sulphate proteoglycans (HSPGs), leading to the formation of productive HSPG/FGF2/FGFR ternary complexes. Presta and coworkers identified, from a virtual screening study of an NCI library, a promising molecule NSC172288 able to inhibit FGF2-FGFR interactions. During my PhD research I designed and performed the synthesis of this compound not described in literature. The major challenge associated was the necessity of planning the synthesis on the base of a poorly described structure. A synthetic pathway for NSC172285 was setup and an efficient method for using HFA trihydrate as electrophilic partner in an aldol reaction, with standard laboratory equipment was developed

Marine Drug Research in China: Selected Papers from the 15-NASMD Conference

The Book covers this whole field, from the discovery of structurally new and bioactive natural products (including biomacromolecules), from marine macro-/micro-organisms, to the pharmacodynamics, pharmacokinetics, metabolisms, and mechanisms of marine-derived lead compounds, both in vitro and in vivo, along with the synthesis and/or structural optimization of marine-derived lead compounds and their structure–activity relationships. Taken together, this Special Issue reprint not only provides inspiration for the discovery of marine-derived novel bioactive compounds, but also sheds light on the further research and development of marine candidate drugs