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Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 47635

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Special Issue Editor

Dr. Dharmendra Kumar Yadav

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College of Pharmacy, Gachon University of Medicine and Science, Incheon City 21924, Korea
Interests: molecular modeling; drug design; computer-aided drug design dynamics simulation of biological networks; plasma medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

It has been observed that small molecules have continuously played an important role in the discovery of novel drugs to treat various kinds of human diseases. The discovery and development of peptide/protein, toxin, and antibody-based drugs will significantly improve the biomedical efficiency of disease specific therapy. In the current drug discovery and development program, structural and mechanistic enzymology is playing a crucial role by making enzymes potential drug targets. Presently, in drug design, prediction and elucidation of biomolecular targets is possible, although their interactions with other molecules and mechanisms of action are unknown. Topics such as bio- and chemo-informatics, small molecules, machine learning, peptide drugs, and modulators may help in improving the knowledge and development of new treatments. A discussion on using novel disease-specific proteins/peptides/toxins/antibodies along with currently available approved drugs as combinatorial treatments is also encouraged in this context.

This thematic issue aims to summarize recent advances in the medicinal chemistry of small molecules, mechanisms of action, and their application in clinical practice for treating various kinds of human diseases. The scope of this thematic issue will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, and structure–activity relationships.

Subtopics: The subtopics may include but are not limited to the following:

Role of small molecules in modulation of multidrug transporters in different diseases;
Drug resistance transporters in bacteria: Hopes from plant-based inhibitors;
Advancement of medicinal chemistry to modulate mechanisms of intrinsic and extrinsic apoptosis, new forms of programmed cell death;
New natural/synthetic small molecule leads to treat human diseases;
Current developments in target-based drug discovery;
Application of modern drug designing tools in small molecule lead optimization;
Challenges in target-based new drug development;
Alternative therapeutics: Novelty and hopes;
Bio- and chemo-informatics, small molecules, machine learning, peptide drugs and modulators, and peptidomimetic compounds applied to drug discovery
Vaccine development

Dr. Dharmendra Kumar Yadav
Guest Editor

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Keywords

drug targets
biomolecular structure and drug design
small molecules
peptide drugs
medicinal chemistry

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Related Special Issue

Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0 in International Journal of Molecular Sciences (9 articles)

Published Papers (12 papers)

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Research

Jump to: Review

13 pages, 1185 KiB

Open AccessArticle

Comparative Antiseizure Analysis of Diverse Natural Coumarin Derivatives in Zebrafish

by Ewelina Kozioł, Krzysztof Jóźwiak, Barbara Budzyńska, Peter A. M. de Witte, Daniëlle Copmans and Krystyna Skalicka-Woźniak

Int. J. Mol. Sci. 2021, 22(21), 11420; https://doi.org/10.3390/ijms222111420 - 22 Oct 2021

Cited by 15 | Viewed by 2492

Abstract

Coumarins are a well-known group of plant secondary metabolites with various pharmacological activities, including antiseizure activity. In the search for new antiseizure drugs (ASDs) to treat epilepsy, it is yet unclear which types of coumarins are particularly interesting as a systematic analysis has not been reported. The current study performed behavioral antiseizure activity screening of 18 different coumarin derivatives in the larval zebrafish pentylenetetrazole (PTZ) model using locomotor measurements. Activity was confirmed for seven compounds, which lowered seizure-like behavior as follows: oxypeucedanin 38%, oxypeucedanin hydrate 74%, notopterol 54%, nodakenetin 29%, hyuganin C 35%, daphnoretin 65%, and pimpinellin 60%. These coumarins, together with nodakenin, underwent further antiepileptiform analysis by local field potential recordings from the zebrafish opticum tectum (midbrain). All of them, except for nodakenetin, showed pronounced antiepileptiform activity, decreasing PTZ-induced elevation in power spectral density (PSD) by 83–89% for oxypeucedanin, oxypeucedanin hydrate, and notopterol, 77% for nodakenin, 26% for nodakenetin, 65% for hyuganin C, 88% for daphnoretin, and 81% for pimpinellin. These data demonstrate the potential of diverse coumarin scaffolds for ASD discovery. Finally, the structural differences between active and inactive coumarins were investigated in silico for oxypeucedanin hydrate and byacangelicin for their interaction with GABA-transaminase, a hypothetical target. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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19 pages, 7543 KiB

Open AccessArticle

Selective Antifungal Activity and Fungal Biofilm Inhibition of Tryptophan Center Symmetrical Short Peptide

by Shuli Chou, Qiuke Li, Hua Wu, Jinze Li, Yung-Fu Chang, Lu Shang, Jiawei Li, Zhihua Wang and Anshan Shan

Int. J. Mol. Sci. 2021, 22(15), 8231; https://doi.org/10.3390/ijms22158231 - 30 Jul 2021

Cited by 8 | Viewed by 2464

Abstract

Candida albicans, an opportunistic fungus, causes dental caries and contributes to mucosal bacterial dysbiosis leading to a second infection. Furthermore, C.albicans forms biofilms that are resistant to medicinal treatment. To make matters worse, antifungal resistance has spread (albeit slowly) in this species. Thus, it has been imperative to develop novel, antifungal drug compounds. Herein, a peptide was engineered with the sequence of RRFSFWFSFRR-NH2; this was named P19. This novel peptide has been observed to exert disruptive effects on fungal cell membrane physiology. Our results showed that P19 displayed high binding affinity to lipopolysaccharides (LPS), lipoteichoic acids (LTA) and the plasma membrane phosphatidylinositol (PI), phosphatidylserine (PS), cardiolipin, and phosphatidylglycerol (PG), further indicating that the molecular mechanism of P19 was not associated with the receptor recognition, but rather related to competitive interaction with the plasma membrane. In addition, compared with fluconazole and amphotericin B, P19 has been shown to have a lower potential for resistance selection than established antifungal agents. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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25 pages, 1973 KiB

Open AccessArticle

Microscopic Interactions of Melatonin, Serotonin and Tryptophan with Zwitterionic Phospholipid Membranes

by Jordi Martí and Huixia Lu

Int. J. Mol. Sci. 2021, 22(6), 2842; https://doi.org/10.3390/ijms22062842 - 11 Mar 2021

Cited by 7 | Viewed by 2796

Abstract

The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10–20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10

^{- 7}

^{2}

/s for the cholesterol-free and cholesterol-rich setups. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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17 pages, 6055 KiB

Open AccessArticle

Heterogeneous Off-Target Effects of Ultra-Low Dose Dimethyl Sulfoxide (DMSO) on Targetable Signaling Events in Lung Cancer In Vitro Models

by Elisa Baldelli, Mahalakshmi Subramanian, Abduljalil M. Alsubaie, Guy Oldaker, Maria Emelianenko, Emna El Gazzah, Sara Baglivo, Kimberley A. Hodge, Fortunato Bianconi, Vienna Ludovini, Lucio Crino’, Emanuel F. Petricoin and Mariaelena Pierobon

Int. J. Mol. Sci. 2021, 22(6), 2819; https://doi.org/10.3390/ijms22062819 - 10 Mar 2021

Cited by 4 | Viewed by 2520

Abstract

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v/v) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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11 pages, 2252 KiB

Open AccessArticle

Trifostigmanoside I, an Active Compound from Sweet Potato, Restores the Activity of MUC2 and Protects the Tight Junctions through PKCα/β to Maintain Intestinal Barrier Function

by Amna Parveen, Seungho Choi, Ju-Hee Kang, Seung Hyun Oh and Sun Yeou Kim

Int. J. Mol. Sci. 2021, 22(1), 291; https://doi.org/10.3390/ijms22010291 - 30 Dec 2020

Cited by 14 | Viewed by 2691

Abstract

Sweet potato (Ipomoea batata) is considered a superfood among vegetables and has been consumed for centuries. Traditionally, sweet potato is used to treat several illnesses, including diarrhea and stomach disorders. This study aimed to explore the protective effect of sweet potato on intestinal barrier function, and to identify the active compounds of sweet potato and their underlying mechanism of action. To this purpose, bioactivity-guided isolation, Western blotting, and immunostaining assays were applied. Interestingly, our bioactivity-guided approach enabled the first isolation and identification of trifostigmanoside I (TS I) from sweet potato. TS I induced mucin production and promoted the phosphorylation of PKCα/β in LS174T human colon cancer cells. In addition, it protected the function of tight junctions in the Caco-2 cell line. These findings suggest that TS I rescued the impaired abilities of MUC2, and protected the tight junctions through PKCα/β, to maintain intestinal barrier function. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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14 pages, 4230 KiB

Open AccessArticle

Inactivation of Infectious Bacteria Using Nonthermal Biocompatible Plasma Cabinet Sterilizer

by Mahmuda Akter, Dharmendra Kumar Yadav, Se Hoon Ki, Eun Ha Choi and Ihn Han

Int. J. Mol. Sci. 2020, 21(21), 8321; https://doi.org/10.3390/ijms21218321 - 6 Nov 2020

Cited by 15 | Viewed by 3296

Abstract

Nonthermal, biocompatible plasma (NBP) is a promising unique state of matter that is effective against a wide range of pathogenic microorganisms. This study focused on a sterilization method for bacteria that used the dielectric barrier discharge (DBD) biocompatible plasma cabinet sterilizer as an ozone generator. Reactive oxygen species play a key role in inactivation when air or other oxygen-containing gases are used. Compared with the untreated control, Escherichia coli(E. coli), Staphylococcus aureus (S. aureus), and Salmonella typhimurium (sepsis) were inhibited by approximately 99%, or were nondetectable following plasma treatment. Two kinds of plasma sterilizers containing six- or three-chamber cabinets were evaluated. There was no noticeable difference between the two configurations in the inactivation of microorganisms. Both cabinet configurations were shown to be able to reduce microbes dramatically, i.e., to the nondetectable range. Therefore, our data indicate that the biocompatible plasma cabinet sterilizer may prove to be an appropriate alternative sterilization procedure. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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Review

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22 pages, 1916 KiB

Open AccessReview

Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives

by Anshul Sharma, Hyo-Kyoung Choi, Yeon-Kye Kim and Hae-Jeung Lee

Int. J. Mol. Sci. 2021, 22(21), 11500; https://doi.org/10.3390/ijms222111500 - 25 Oct 2021

Cited by 23 | Viewed by 4020

Abstract

Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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21 pages, 4049 KiB

Open AccessReview

B Cell Lymphoma 2: A Potential Therapeutic Target for Cancer Therapy

by Manzar Alam, Sabeeha Ali, Taj Mohammad, Gulam Mustafa Hasan, Dharmendra Kumar Yadav and Md. Imtaiyaz Hassan

Int. J. Mol. Sci. 2021, 22(19), 10442; https://doi.org/10.3390/ijms221910442 - 28 Sep 2021

Cited by 49 | Viewed by 4431

Abstract

Defects in the apoptosis mechanism stimulate cancer cell growth and survival. B cell lymphoma 2 (Bcl-2) is an anti-apoptotic molecule that plays a central role in apoptosis. Bcl-2 is the founding constituent of the Bcl-2 protein family of apoptosis controllers, the primary apoptosis regulators linked with cancer. Bcl-2 has been identified as being over-expressed in several cancers. Bcl-2 is induced by protein kinases and several signaling molecules which stimulate cancer development. Identifying the important function played by Bcl-2 in cancer progression and development, and treatment made it a target related to therapy for multiple cancers. Among the various strategies that have been proposed to block Bcl-2, BH3-mimetics have appeared as a novel group of compounds thanks to their favorable effects on many cancers within several clinical settings. Because of the fundamental function of Bcl-2 in the regulation of apoptosis, the Bcl-2 protein is a potent target for the development of novel anti-tumor treatments. Bcl-2 inhibitors have been used against several cancers and provide a pre-clinical platform for testing novel therapeutic drugs. Clinical trials of multiple investigational agents targeting Bcl-2 are ongoing. This review discusses the role of Bcl-2 in cancer development; it could be exploited as a potential target for developing novel therapeutic strategies to combat various types of cancers. We further highlight the therapeutic activity of Bcl-2 inhibitors and their implications for the therapeutic management of cancer. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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13 pages, 1422 KiB

Open AccessReview

Protease Inhibition—An Established Strategy to Combat Infectious Diseases

by Daniel Sojka, Pavla Šnebergerová and Luïse Robbertse

Int. J. Mol. Sci. 2021, 22(11), 5762; https://doi.org/10.3390/ijms22115762 - 28 May 2021

Cited by 14 | Viewed by 3865

Abstract

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays—malaria and COVID-19. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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18 pages, 4299 KiB

Open AccessReview

Bruton’s Tyrosine Kinase Targeting in Multiple Myeloma

by Max Von Suskil, Kazi Nasrin Sultana, Weam Othman Elbezanti, Omar S. Al-Odat, Robert Chitren, Amit K. Tiwari, Kishore B. Challagundla, Sandeep Kumar Srivastava, Subash C. Jonnalagadda, Tulin Budak-Alpdogan and Manoj K. Pandey

Int. J. Mol. Sci. 2021, 22(11), 5707; https://doi.org/10.3390/ijms22115707 - 27 May 2021

Cited by 14 | Viewed by 4532

Abstract

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones’ hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton’s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones’ interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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12 pages, 845 KiB

Open AccessReview

Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs

by Hyeon Jin Kim, Mi Suk Jeong and Se Bok Jang

Int. J. Mol. Sci. 2021, 22(8), 4242; https://doi.org/10.3390/ijms22084242 - 19 Apr 2021

Cited by 11 | Viewed by 4585

Abstract

The influenza virus causes human disease on a global scale and significant morbidity and mortality. The existing vaccination regime remains vulnerable to antigenic drift, and more seriously, a small number of viral mutations could lead to drug resistance. Therefore, the development of a new additional therapeutic small molecule-based anti-influenza virus is urgently required. The NS1 influenza gene plays a pivotal role in the suppression of host antiviral responses, especially by inhibiting interferon (IFN) production and the activities of antiviral proteins, such as dsRNA-dependent serine/threonine-protein kinase R (PKR) and 2′-5′-oligoadenylate synthetase (OAS)/RNase L. NS1 also modulates important aspects of viral RNA replication, viral protein synthesis, and virus replication cycle. Taken together, small molecules that target NS1 are believed to offer a means of developing new anti-influenza drugs. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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39 pages, 3373 KiB

Open AccessReview

Therapeutic Advances in Oncology

by Jinsha Liu, Priyanka Pandya and Sepideh Afshar

Int. J. Mol. Sci. 2021, 22(4), 2008; https://doi.org/10.3390/ijms22042008 - 18 Feb 2021

Cited by 27 | Viewed by 8055

Abstract

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases)

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