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... order to compare docking scores of known CA-IX inhibitors with selected compounds from our study, we docked 14 known CA-IX inhibitors [38][39][40][41][42][43][44] at the active site of the target. Docking scores and chemical structures of these compounds are found in the range of À5.66 to À6.79 kcal/mole (Table S2). ...
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... Carbonic anhydrases are a ubiquitous metalloenzyme family containing zinc in their active sites. CA-IX is a well-known tumor-associated isoenzyme which is highly overexpressed in different types of cancers, with a limited number in normal tissues [24]. Thus, it is considered a promising drug target for treating cancer. ...
A novel series of tri-aryl imidazole derivatives 5a–n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3–1.3 μM, and selectivity ratio for hCA IX over hCA XII = 5–12) relative to acetazolamide (Ki = 0.03 μM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.
... Regardless of the numerous experimental studies available on CA IX and its complexes, there is still only a few systematic MD models and simulations [12][13][14][15] . From a computational point of view, drug design methodologies combined with rigid-body docking and MD simulation are promising to investigate binding site(s), binding affinity and enzyme-ligand interactions [16][17][18] . Therefore, in this work, molecular docking studies were performed to additionally rank the ligands and validate the inverse QSPR. ...
In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logkw) and inhibitory activity (logKi) were used as drug properties. Genetic algorithm-partial least squares (GA-PLS) provided a QSPR model with high prediction capability employing only seven molecular descriptors. As a proof-of-concept, optimal drug structure was obtained by inverting the model with respect to reference drug properties. 3509 ligands were ranked accordingly. Top 10 ligands were further validated through molecular docking. Large-scale MD simulations were performed to test the stability of structures of selected ligands obtained through docking complemented with biophysical experiments.
... Molecular modeling approaches, such as molecular docking calculations, are generally used techniques to qualify and quantify the important information about the ligand-receptor interaction analysis on atomistic level. There are many studies using these approaches integrated to human carbonic anhydrases (hCA) in order to clarify the molecular mechanism of action and bioactive conformation of proposed compounds at the binding site of the protein [43][44][45][46][47][48][49] . Since there is no experimental study yet on stable state (hydrolyzed/nonhydrolyzed) of studied compounds from lactone moiety at the binding pocket of the CAs, both hydrolyzed and nonhydrolyzed forms were considered at the docking. ...
New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-N-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-2H-chromene-3-carboxamide (e11) exhibited a selective inhibitory action against hCA IX with the Ki of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms.
... In addition, their effort was expanded on solving a crystal structure of PARP-1 catalytic domain (with a resolution of 2.63 Å) in complex with a high binding affinity inhibitor (IC 50 of 1.92 nM) (Ye et al., 2013). Our main aim in this study was to represent the importance of the theoretical approaches for discovery of novel PARP-1 inhibitors using high-throughput virtual screening (HTVS) of synthesized small molecule databases and to identify their mechanism of actions (Ekhteiari Mirza, Salmas, Fatmi, & Durdagi, 2016; Salmas, Mestanoglu, Yurtsever, Noskov, & Durdagi, 2015; Salmas, Senturk, Yurtsever, & Durdagi, 2015). Proposed compounds from a ligand database (>250,000 synthesized ligands from Otava database) are tested by in vitro studies in order to verify the correct predictions of theoretical approaches. ...
... All ligands were found to be in an acceptable range of the ADME standards. Virtual screening of large ligand database against specific target structures to discover novel lead compounds has been successfully applied by our group (Mirza et al., 2016; Salmas, Senturk, et al., 2015) and different laboratories recently in the literature (Hannigan et al., 2013). In this study, 257,951 small molecules retrieved from the Otava database were virtually screened at the catalytic domain of the PARP-1 enzyme Table 2. IFD scores of the selected compounds. ...
Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. 257951 ligands from Otava database were screened at the binding pocket of PARP-1 using high throughput virtual screening (HTVS) techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e., Glide/SP, Glide/XP, Induced Fit Docking- IFD, and Quantum Mechanics Polarized Ligand Docking- QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 µM and 63 µM against PARP-1 target, respectively. The molecular mechanism analysis, Free Energy Perturbation calculations using long multiple molecular dynamics (MD) simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.
... It carries out proteolysis of the polyprotein through its serine protease N-terminal domain which is essential enzymatic reactions for viral replication. Precise and computationally competent virtual screening can act as a potential step towards the future "on-shelf" dengue virus drugs [50][51][52]. Consequently, we have identified few novel inhibitors by in silico screening of drug-like library of compounds (around 18 million) from the ZINC database using Glide docking programs. Docking results of top-five compounds in our study show strong predicted binding affinity for the catalytically important residues of NS3. ...
... Among the 16 isoenzymes described up to now in mammalian organisms, CA I and CA II are present at high concentrations in the cytosol of erythrocytes and the gastrointestinal tract [7][8][9][10][11] . CA IX is found in tumor cells and absent (or are present in very limited amount) in normal tissues [12][13][14][15] . CA isoenzymes constitute interesting targets for the design of pharmacological agents that are useful in the treatment or prevention of a variety of disorders such as glaucoma, epilepsy, as diuretics or antitumor agents/diagnostic tools 7,14 . ...
A series of hydroxylic compounds (1-10, NK-154 and NK-168) have been assayed for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic isozymes I, II and tumor-associated isozyme IX. The investigated compounds showed inhibition constants in the range of 0.068-4003, 0.012-9.9 and 0.025-115 μm at the hCA I, hCA II and hCA IX enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are calculated using scoring algorithms, namely Glide/induced fit docking. The inhibitory potencies of the novel compounds were analyzed at the human isoforms hCA I, hCA II and hCA IX as targets and the KI values were calculated.
The PARP research on cancer and ischemia is advancing at a breakneck pace. Olaparib, Rucaparib, Niraparib, and Talazoparib are the four PARP1 inhibitors currently on the market, according to the FDA. All of these compounds are non-selective PARP1 inhibitors. Novel and selective PARP1 inhibitors are desperately needed right now. A small molecule database (Specs SC) was used to find new selective lead inhibitors of PARP1 in this study. The 9-anilinoacridine scaffold is a new fragment that is employed as a PARP1 inhibitor and anti-proliferative drug. Thus, 21 compounds containing 9-Anilinoacridine fragments were discovered and virtually tested in the binding site of target protein PARP1 based on text mining studies. In molecular dynamics (MD) simulations, compounds with high docking scores were employed. The anticipated binding energies were compared to known PARP1 inhibitors using free energy calculations. Docking study revealed that among all 21 compounds 1v showed highest g score. Prime MMGBSA analysis gave the relative binding energies of 1v. The essential amino acid interactions of these newly discovered hits in the binding pocket were also studied in depth in order to gain a better understanding of the structural properties required for next-generation PARP1 inhibitors. Thus, we identified novel 9-Anilinoacridine-based hits against the PARP1 enzyme using a mix of text-mining and integrated molecular modelling techniques.
Computer-aided drug design includes an ensemble of different in silico strategies that represent valuable tools for facilitating the discovery and optimization of novel hit compounds endowed with biological activity toward the desired target proteins. Due to the various pathological implications of carbonic anhydrases (CAs), especially in the development and progression of cancer, molecular modeling techniques have been widely applied for the identification of new CA inhibitors. In this chapter, after providing the reader with a brief introduction to computational methods in drug design, we summarize the results of the main virtual screening (VS) studies that led to the discovery of novel ligands of different CA isoforms, describing the various receptor-based and ligand-based approaches employed. Moreover, we report the results of retrospective analyses in which CAs and their known ligands have been used to validate the performance of various VS methods in hit identification. The present chapter should provide the reader with a panoramic view of the most used and reliable in silico techniques to be applied in the search for novel CA inhibitors.
One of the important steps in the enzyme catalyzed reaction is the binding of ligand or substrate to an enzyme (target or macromolecule). The study of their interactions using molecular docking methods to explore the ligand conformations adopted within the binding sites of macromolecular targets forms the basis for a rational drug design strategy. This approach is used in drug discovery and medicinal chemistry to identify or design small molecules against specific targets, for therapeutic interventions, for infectious diseases, antibiotic resistance, cancer, or cardiovascular diseases, and many more. Huge amounts of money and many years are spent to introduce a medicine into the commercial market; hence, it becomes necessary for a scientist to explore new cost and time saving ways to launch a drug into the market. The use of molecular docking approach to identify drug candidate against infectious diseases has now become one of the important steps in drug designing.
This chapter highlights five aspects of the use of molecular docking for drug design: structure-based drug design (multiple molecules docked against a target), ligand-based drug design (exploration of molecular descriptors), fragment-based drug design (expansion or linkage of small fragments identified against a target to generate lead molecule), reverse or inverse drug designing (screening of potential interacting proteins against a compound of interest), and drug repurposing (identification of new uses for approved drugs). We would further discuss several successful cases of molecular docking and drug design studies including drugs for the treatment of HIV, tuberculosis, influenza, malaria, antibiotic resistance, and other prevalent diseases such as cancer.
Dopamine D2 receptor plays a pivotal role in nervous systems. Its dysfunction leads to the schizophrenia, Parkinson’s diseases and drug addiction. Since the crystal structure of the D2R was not solved yet, discovering of potent and highly selective anti-psychotic drugs faces with main challenges. In the current study, we modeled the 3D structure of the D2R based on a recently crystallized structure of the dopamine D3 receptor. These receptors share a high amino acid sequence homology (> 70%). The interaction of the modeled receptor with well-known atypical and typical anti-psychotic drugs and the inhibition mechanisms of drugs at the catalytic domain were studied via atomistic molecular dynamic (MD) simulations. Our results revealed that, class-I and class-II forms of atypical and typical D2R antagonists follow different pathways in the inhibition of the D2R.
