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Small Molecule Drug Design
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Small Molecule Drug Design

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 31007

Special Issue Editor

Prof. Dr. Adel Nefzi

E-Mail Website
Guest Editor
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA
Interests: organic chemistry; medicinal chemistry; small molecules; drug-like compounds; tethered and fused diazacyclic compounds; heterocyclic peptidomimetics; combinatorial chemistry; solid phase organic synthesis

Special Issue Information

Dear Colleagues,

The last two decades have witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signalling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput mechanism-based biological assays. How does one approach the challenge of generating diverse small-molecule libraries that are likely to provide robust hits against a wide variety of molecular targets and, at the same time, are sound platforms for rapid optimization, affording potent and selective chemical probes that reside within a novel and biologically relevant chemical space? Since no single library can possibly occupy the entire universe of chemical space, there is a widespread agreement that increased access to chemical diversity is needed to target the whole biological space and thus increase the number of targets that are considered “druggable.” The search for new therapeutic entities can proceed along three principal paths of exploration: random walks, building on existing active structures, and using macromolecules as templates for molecular assembly.

Furthermore, there are several practical considerations involved in the efficient production of new entities designed to provide novel chemical probes. For example, the starting materials should be readily available and inexpensive; the synthetic steps must be straightforward, efficient, and reproducible on a multigram scale, the intermediates and final target species must be readily purified, preferably resulting from clean, high-yielding reactions that require minimal purification.

Because of high attrition rates, especially during the clinical phases of drug development, more attention is needed in the early drug design process on selecting candidate drugs whose physicochemical properties are predicted to result in fewer complications during development and, hence, are more likely to lead to an approved, marketed drug. Techniques such as in vitro experiments complemented with computation methods are increasingly used in early drug discovery to select compounds with more favorable ADME and toxicological profiles.

Prof. Adel Nefzi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug design
  • diversity-oriented synthesis
  • combinatorial chemistry
  • computationally guided synthesis
  • drug-like compounds
  • computer modeling techniques

Published Papers (8 papers)

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Research

21 pages, 2758 KiB  
Article
Nuclear Receptors Are Differentially Expressed and Activated in KAIMRC1 Compared to MCF7 and MDA-MB231 Breast Cancer Cells
by Atef Nehdi, Rizwan Ali, Alshaimaa Alhallaj, Hajar Alzahrani, Nosaibah Samman, Abdullah Mashhour, Omar Baz, Tlili Barhoumi, Bandar Alghanem, Abdullatif Khan, Lolwah Alriyees and Mohamed Boudjelal
Molecules 2019, 24(11), 2028; https://doi.org/10.3390/molecules24112028 - 28 May 2019
Cited by 6 | Viewed by 3875
Abstract
We recently established a KAIMRC1 cell line that has unique features compared to the known breast cancer cell lines, MCF7 and MDA-MB231. To characterize it further, we investigated the expression profile of nuclear receptors and their respective co-factors in these cell lines. We [...] Read more.
We recently established a KAIMRC1 cell line that has unique features compared to the known breast cancer cell lines, MCF7 and MDA-MB231. To characterize it further, we investigated the expression profile of nuclear receptors and their respective co-factors in these cell lines. We confirm that in contrast to the triple negative cell line MDA-MB231, the MCF7 and KAIMRC1 are estrogen receptor alpha (ERa) and progesterone receptor alpha (PRa) positive, with significant lower expression of these receptors in KAIMRC1. KAIMRC1 cell is a vitamin D receptor (VDR) negative and V-ErbA-Related Protein 2 (EAR2) positive in contrast to MCF7 and MDA-MB231. Remarkably, the histone deacetylases (HDACs) are highly expressed in KAIRMC1 with HDAC6 and HDAC 7 are exclusively expressed in KAIMRC1 while thyroid hormone receptor-associated protein 80 (TRAP80), telomeric DNA binding protein 1 (TBP1) and TGF-beta receptor interacting protein (TRIP1) are absent in KAIMRC1 but present in MCF7 and MDA-MB231. In a luciferase reporter assay, the ERa coexpression is needed for estrogen receptor element (ERE)-luciferase activation by estradiol in KAIMRC1 but not in MCF7. The co-expression of exogenous Liver X receptor alpha (LXRa)/retinoid X receptor alpha (RXRa) are necessary for LXR responsive element (LXRE) activation by the GW3696 in the three cell lines. However, the activity of peroxisome proliferator-activated receptor response element (PPARE)-tk-luciferase reporter increased when peroxisome proliferator-activated receptors alpha (PPARa)/RXRa were coexpressed but the addition of PPARa agonist (GW7647) did not stimulate further the reporter. The signal of the PPARE reporter increased in a dose-dependent manner with rosiglitazone (PPARg agonist) in KAIMRC1, MCF7, and MDA-MB231 when the proliferator-activated receptors gamma (PPARg)/RXRa receptors were cotransfected. Retinoic acid-induced activation of retinoic acid receptor response element (RARE)-tk-luciferase is dependent on exogenous expression of retinoic acid receptor alpha (RARa)/RXRa heterodimer in MDA-MB 231 but not in MCF7 and KAIMRC1 cell lines. In the three cell lines, Bexarotene-induced retinoid X receptor response element (RXRE)-luciferase reporter activation was induced only if the RXRa/LXRa heterodimer were co-expressed. The vitamin D receptor response element (VDRE)-luciferase reporter activity showed another distinct feature of KAIMRC1, where only co-expression of exogenous vitamin D receptor (VDR)/RXRa heterodimer was sufficient to reach the maximum rate of activation of VDRE reporter. In the proliferation assay, nuclear receptors ligands showed a distinct effect on KAIMRC1 compared to MCF7 and MDA-MB231. Growth inhibition effects of used ligands suggest that KAIMRC1 correlate more closely to MDA-MB231 than MCF7. Vitamin D3, rosiglitazone, novel RXR compound (RXRc) and PPARa compound (GW6471) have the most profound effects. In conclusion, we showed that nuclear receptors are differentially expressed, activated and also their ligand produced distinct effects in KAIMRC1 compared to MCF7 and MDA-MB231. This finding gives us confidence that KAIMRC1 has a unique biological phenotype. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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18 pages, 10220 KiB  
Article
Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors
by Siyu Zhu, Chaozai Zhang, Lina S. Huang, Xing-Quan Zhang, Yan Xu, Xiong Fang, Jiao Zhou, Meixian Wu, Robert T. Schooley, Ziwei Huang and Jing An
Molecules 2019, 24(8), 1465; https://doi.org/10.3390/molecules24081465 - 13 Apr 2019
Cited by 9 | Viewed by 4010
Abstract
Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to [...] Read more.
Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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14 pages, 2453 KiB  
Article
Identification of Bis-Cyclic Guanidines as Antiplasmodial Compounds from Positional Scanning Mixture-Based Libraries
by David L. Perry, Jr., Bracken F. Roberts, Ginamarie Debevec, Heather A. Michaels, Debopam Chakrabarti and Adel Nefzi
Molecules 2019, 24(6), 1100; https://doi.org/10.3390/molecules24061100 - 20 Mar 2019
Cited by 8 | Viewed by 2765
Abstract
The screening of more than 30 million compounds derived from 81 small molecule libraries built on 81 distinct scaffolds identified pyrrolidine bis-cyclic guanidine library (TPI-1955) to be one of the most active and selective antiplasmodial libraries. The screening of the positional scanning library [...] Read more.
The screening of more than 30 million compounds derived from 81 small molecule libraries built on 81 distinct scaffolds identified pyrrolidine bis-cyclic guanidine library (TPI-1955) to be one of the most active and selective antiplasmodial libraries. The screening of the positional scanning library TPI-1955 arranged on four sets of sublibraries (26 + 26 + 26 + 40), totaling 120 samples for testing provided information about the most important groups of each variable position in the TPI-1955 library containing 738,192 unique compounds. The parallel synthesis of the individual compounds derived from the deconvolution of the positional scanning library led to the identification of active selective antiplasmodial pyrrolidine bis-cyclic guanidines. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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11 pages, 6922 KiB  
Article
Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO-1) Inhibitors Based on Ortho-Naphthaquinone-Containing Natural Product
by Hongchuan Zhao, Pu Sun, Wei Guo, Yi Wang, Ao Zhang, Linghua Meng and Chunyong Ding
Molecules 2019, 24(6), 1059; https://doi.org/10.3390/molecules24061059 - 18 Mar 2019
Cited by 14 | Viewed by 3791
Abstract
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body’s immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have [...] Read more.
There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body’s immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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18 pages, 4163 KiB  
Article
Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors
by Cécile Baudoin-Dehoux, Tessa Castellan, Frédéric Rodriguez, Arnaud Rives, Fabien Stauffert, Virginie Garcia, Thierry Levade, Philippe Compain and Yves Génisson
Molecules 2019, 24(2), 354; https://doi.org/10.3390/molecules24020354 - 19 Jan 2019
Cited by 5 | Viewed by 4379
Abstract
A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward [...] Read more.
A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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31 pages, 1990 KiB  
Article
Small Multitarget Molecules Incorporating the Enone Moiety
by Thalia Liargkova, Nikolaos Eleftheriadis, Frank Dekker, Efstathia Voulgari, Constantinos Avgoustakis, Marina Sagnou, Barbara Mavroidi, Maria Pelecanou and Dimitra Hadjipavlou-Litina
Molecules 2019, 24(1), 199; https://doi.org/10.3390/molecules24010199 - 07 Jan 2019
Cited by 16 | Viewed by 4814
Abstract
Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since “one drug-one target” therapies have failed [...] Read more.
Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since “one drug-one target” therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis-etherified bis-chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone b4 presents significant inhibitory activity against the 15-human LOX with an IC50 value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. Bis-etherified chalcone c12 is the most potent inhibitor of AChE within the bis-etherified bis-chalcones followed by c11. Bis-chalcones c11 and c12 were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active bis-chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds c2 and c4 display additional protective actions against Alzheimer’s disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of c11 (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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15 pages, 4236 KiB  
Article
Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs
by Attila Márió Remete and Loránd Kiss
Molecules 2019, 24(1), 161; https://doi.org/10.3390/molecules24010161 - 03 Jan 2019
Cited by 4 | Viewed by 3153
Abstract
Stereocontrolled synthesis of some amino acid-based carbocyclic nucleoside analogs containing ring C=C bond has been performed on β- and γ-lactam basis. Key steps were N-arylation of readily available β- or γ-lactam-derived amino ester isomers and amino alcohols with 5-amino-4,6-dichloropyrimidine; ring closure of [...] Read more.
Stereocontrolled synthesis of some amino acid-based carbocyclic nucleoside analogs containing ring C=C bond has been performed on β- and γ-lactam basis. Key steps were N-arylation of readily available β- or γ-lactam-derived amino ester isomers and amino alcohols with 5-amino-4,6-dichloropyrimidine; ring closure of the formed adduct with HC(OMe)3 and nucleophilic displacement of chlorine with various N-nucleophiles in the resulting 6-chloropurine moiety. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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17 pages, 4802 KiB  
Article
Neo-5,22E-Cholestadienol Derivatives from Buthus martensii Karsch and Targeted Bactericidal Action Mechanisms
by Biyu Lv, Weiping Yin, Jiayu Gao, Huaqing Liu, Kun Liu, Jie Bai and Qiangqiang Yang
Molecules 2019, 24(1), 72; https://doi.org/10.3390/molecules24010072 - 26 Dec 2018
Cited by 2 | Viewed by 3100
Abstract
The discovery and search for new antimicrobial molecules from insects and animals that live in polluted environments is a very important step in the scientific search for solutions to the current problem of antibiotic resistance. Previously, we have reported that the secondary metabolite [...] Read more.
The discovery and search for new antimicrobial molecules from insects and animals that live in polluted environments is a very important step in the scientific search for solutions to the current problem of antibiotic resistance. Previously, we have reported that the secondary metabolite with the antibacterial action discovered in scorpion. The current study further isolated three new compounds from Buthus martensii karsch, while compounds 1 and 2 possessed 5,22E-cholestadienol derivatives whose structure demonstrated broad spectrum bactericide activities. To explore the antibacterial properties of these new compounds, the result shows that compound 2 inhibited bacterial growth of both S. aureus and P. aeruginosa in a bactericidal rather than a bacteriostatic manner (MBC/MIC ratio ≤ 2). Similarly, with compound 1, a ratio of MBC/MIC ≤ 2 indicates bactericidal activity inhibited bacterial growth of P. aeruginosa. Remarkably, this suggests that two compounds can be classified as bactericidal agents against broad spectrum bactericide activities for 5,22E-cholestadienol derivatives from Buthus martensii karsch. The structures of compounds 1–3 were established by comprehensive spectra analysis including two-dimensional nuclear magnetic resonance (2D-NMR) and high-resolution electrospray ionization-mass spectrometry (HRESI-MS) spectra. The antibacterial mechanism is the specific binding (various of bonding forces between molecules) using compound 1 or 2 as a ligand based on the different receptor proteins’—2XRL or 1Q23—active sites from bacterial ribosome unit A, and thus prevent the synthesis of bacterial proteins. This unique mechanism avoids the cross-resistance issues of other antibacterial drugs. Full article
(This article belongs to the Special Issue Small Molecule Drug Design)
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