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Directed Drug Design and Molecular Therapy

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

Deadline for manuscript submissions: closed (1 August 2019) | Viewed by 56778

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Prof. Dr. Mahesh Narayan

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Department of Chemistry and Biochemistry, University of Texas at El Paso (UTEP), El Paso, TX 79968, USA
Interests: protein folding; docking; halogen bonding; reactive oxygen species; neurodegenerative disorders; drug-discovery; chemical education
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Dear Colleagues,

The field of drug discovery is experiencing a renaissance. It was not long ago that the pharmaceutical giants reported a gloomy outlook, with no new therapeutics coming into the market. Pharma lines had dried with the soils of tropics having being mined bare for some time. The ocean floor represented an avenue, but it was not easy to harvest. However, the overcast forecast propelled the biomedical community to dig deep and looks for alternative avenues to keep the hits coming. Particularly noteworthy in this light were (and continue to be) the efforts to gain traction into better understanding ligand:receptor interactions using in silico approaches. A second avenue is the development of mechanisms to elucidate the dynamics of receptors and the folding forces that are key to their integrity. A third is the use of unnatural atoms in receptors to unravel their biology. A case in point is the extensive use of Selenium atoms in place of cytseine sulfurs to clarify the functional roles of proteins in complex environments. Such steps are pivotal in directed drug design and improve the odds of a successful outcome (hit), rather than the alternative approach of simply screening millions of compounds. Finally, a fourth approach that has emerged on the horizon is that of tailored therapies. This mechanism takes into account the single nucleotide polymorphisms (SNPs) in individuals that compromise therapeutic outcomes. By examining enzymes such as the cytochrome P450 family for polymorphisms and by also profiling the metabolic products of drug candidates as a function of the SNP, a better therapeutic regimen can be designed.

In sum and substance, clearly the ability to resolve, at a molecular level, the chemistry between a biological host and its ligand guest is key towards bettering the biomedical prospects of disease intervention.

Prof. Mahesh Narayan
Guest Editor

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Keywords

in silico drug-design
drug-receptor interaction
molecular dynamics
single nucleotide polymorphisms

Published Papers (10 papers)

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Research

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15 pages, 4251 KiB

Open AccessArticle

Comparative Studies of the Dynamics Effects of BAY60-2770 and BAY58-2667 Binding with Human and Bacterial H-NOX Domains

by Rana Rehan Khalid, Muhammad Tahir ul Qamar, Arooma Maryam, Ayesha Ashique, Farooq Anwar, Mohammed H. Geesi and Abdul Rauf Siddiqi

Molecules 2018, 23(9), 2141; https://doi.org/10.3390/molecules23092141 - 25 Aug 2018

Cited by 18 | Viewed by 4445

Abstract

Soluble guanylate cyclase (sGC) is a key enzyme implicated in various physiological processes such as vasodilation, thrombosis and platelet aggregation. The enzyme’s Heme-Nitric oxide/Oxygen (H-NOX) binding domain is the only sensor of nitric oxide (NO) in humans, which on binding with NO activates sGC to produce the second messenger cGMP. H-NOX is thus a hot target for drug design programs. BAY60-2770 and BAY58-2667 are two widely studied activators of sGC. Here we present comparative molecular dynamics studies to understand the molecular details characterizing the binding of BAY60-2770 and BAY58-2667 with the human H-NOX (hH-NOX) and bacterial H-NOX (bH-NOX) domains. HartreeFock method was used for parametrization of both the activators. A 50 ns molecular dynamics (MD) simulation was run to identify the functionally critical regions of the H-NOX domains. The CPPTRAJ module was used for analysis. BAY60-2770 on binding with bH-NOX, triggered rotational movement in signaling helix F and significant dynamicity in loops α and β, but in hH-NOX domain the compound showed relatively lesser aforementioned structural fluctuations. Conversely, hH-NOX ligated BAY58-2667 experienced highest transitions in its helix F due to electrostatic interactions with D84, T85 and R88 residues which are not conserved in bH-NOX. These conformational transformations might be essential to communicate with downstream PAS, CC and cyclase domains of sGC. Comparative MD studies revealed that BAY bound bHNOX dynamics varied from that of hH-NOX, plausibly due to some key residues such as R40, F74 and Y112 which are not conserved in bacteria. These findings will help to the design of novel drug leads to cure diseases associated to human sGC. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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16 pages, 4352 KiB

Open AccessArticle

Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency

by Megan E. Meuser, Michael B. Murphy, Adel A. Rashad and Simon Cocklin

Molecules 2018, 23(8), 1940; https://doi.org/10.3390/molecules23081940 - 03 Aug 2018

Cited by 11 | Viewed by 5322

Abstract

The entry of HIV-1 into permissible cells remains an extremely attractive and underexploited therapeutic intervention point. We have previously demonstrated the ability to extend the chemotypes available for optimization in the entry inhibitor class using computational means. Here, we continue this effort, designing and testing three novel compounds with the ability to inhibit HIV-1 entry. We demonstrate that alteration of the core moiety of these entry inhibitors directly influences the potency of the compounds, despite common proximal and distal groups. Moreover, by establishing for the first time a surface plasmon resonance (SPR)-based interaction assay with soluble recombinant SOSIP Env trimers, we demonstrate that the off-rate (k_d) parameter shows the strongest correlation with potency in an antiviral assay. Finally, we establish an underappreciated relationship between the potency of a ligand and its degree of electrostatic complementarity (EC) with its target, the Env complex. These findings not only broaden the chemical space in this inhibitor class, but also establish a rapid and simple assay to evaluate future HIV-1 entry inhibitors. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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17 pages, 1759 KiB

Open AccessArticle

Assessing the Antioxidant Properties of Larrea tridentata Extract as a Potential Molecular Therapy against Oxidative Stress

by Rachid Skouta, Karla Morán-Santibañez, Carlos A. Valenzuela, Abimael H. Vasquez and Karine Fenelon

Molecules 2018, 23(7), 1826; https://doi.org/10.3390/molecules23071826 - 23 Jul 2018

Cited by 27 | Viewed by 6104

Abstract

Oxidative stress has been linked to neurodegenerative diseases such as Huntington’s, Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis diseases. Larrea tridentata (LT) also known as Creosote Bush is an evergreen shrub found in the Chihuahuan desert which has been used medicinally by Native American tribes in southwestern North America and the Amerindians of South America. However, studies of the antioxidant capacity of the crude extract of LT towards the discovery of novel molecular therapies bearing antioxidants and drug-like properties are lacking. In this study, we assessed the antioxidant properties of Larrea tridentata, collected specifically from the Chihuahuan desert in the region of El Paso del Norte, TX, USA. LT phytochemicals were obtained from three different extracts (ethanol; ethanol: water (60:40) and water). Then the extracts were evaluated in eight different assays (DPPH, ABTS, superoxide; FRAP activity, nitric oxide, phenolic content, UV visible absorption and cytotoxicity in non-cancerous HS27 cells). The three extracts were not affecting the HS27 cells at concentrations up to 120 µg/mL. Among the three extracts, we found that the mixture of ethanol: water (60:40) LT extract has the most efficient antioxidant properties (IC₅₀ (DPPH at 30 min) = 111.7 ± 3.8 μg/mL; IC₅₀ (ABTS) = 8.49 ± 2.28 μg/mL; IC₅₀ (superoxide) = 0.43 ± 0.17 μg/mL; IC₅₀ (NO) = 230.4 ± 130.4 μg/mL; and the highest phenolic content was estimated to 212.46 ± 7.05 mg GAE/L). In addition, there was a strong correlation between phenolic content and the free-radical scavenging activity assays. HPLC-MS study identified nine compounds from the LT-ethanol: water extract including Justicidin B and Beta peltain have been previously reported as secondary metabolites of Larrea tridentata. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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16 pages, 2966 KiB

Open AccessArticle

Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

by Felipe Rodriguez, Eva Iniguez, Guadalupe Pena Contreras, Haidar Ahmed, Thadeu E. M. M. Costa, Rachid Skouta and Rosa A. Maldonado

Molecules 2018, 23(7), 1626; https://doi.org/10.3390/molecules23071626 - 04 Jul 2018

Cited by 6 | Viewed by 3862

Abstract

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC₅₀ 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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15 pages, 4581 KiB

Open AccessArticle

Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1

by Ming He, Qianyi Yang, Allison B. Norvil, David Sherris and Humaira Gowher

Molecules 2018, 23(7), 1615; https://doi.org/10.3390/molecules23071615 - 03 Jul 2018

Cited by 2 | Viewed by 4549

Abstract

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 μM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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17 pages, 4796 KiB

Open AccessArticle

The Mechanism for siRNA Transmembrane Assisted by PMAL

by Yanfei Lu, Jipeng Li, Nan Su and Diannan Lu

Molecules 2018, 23(7), 1586; https://doi.org/10.3390/molecules23071586 - 29 Jun 2018

Cited by 2 | Viewed by 2995

Abstract

The capacity of silencing genes makes small interfering RNA (siRNA) appealing for curing fatal diseases. However, the naked siRNA is vulnerable to and degraded by endogenous enzymes and is too large and too negatively charged to cross cellular membranes. An effective siRNA carrier, PMAL (poly(maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine), has been demonstrated to be able to assist siRNA transmembrane by both experiments and molecular simulation. In the present work, the mechanism of siRNA transmembrane assisted by PMAL was studied using steered molecular dynamics simulations based on the martini coarse-grained model. Here two pulling rates, i.e., 10⁻⁶ and 10⁻⁵ nm·ps⁻¹, were chosen to imitate the passive and active transport of siRNA, respectively. Potential of mean force (PMF) and interactions among siRNA, PMAL, and lipid bilayer membrane were calculated to describe the energy change during siRNA transmembrane processes at various conditions. It is shown that PMAL-assisted siRNA delivery is in the mode of passive transport. The PMAL can help siRNA insert into lipid bilayer membrane by lowering the energy barrier caused by siRNA and lipid bilayer membrane. PMAL prefers to remain in the lipid bilayer membrane and release siRNA. The above simulations establish a molecular insight of the interaction between siRNA and PMAL and are helpful for the design and applications of new carriers for siRNA delivery. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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24 pages, 10744 KiB

Open AccessArticle

Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1

by Shin-ichi Kawaguchi, Yuhei Gonda, Takuya Yamamoto, Yuki Sato, Hiroyuki Shinohara, Yohsuke Kobiki, Atsuhiko Ichimura, Takashi Dan, Motohiro Sonoda, Toshio Miyata, Akiya Ogawa and Tadayuki Tsujita

Molecules 2018, 23(4), 885; https://doi.org/10.3390/molecules23040885 - 11 Apr 2018

Cited by 5 | Viewed by 5694

Abstract

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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10 pages, 909 KiB

Open AccessArticle

Semisynthesis and Biological Evaluation of Oleanolic Acid 3-O-β-d-Glucuronopyranoside Derivatives for Protecting H9c2 Cardiomyoblasts against H₂O₂-Induced Injury

by Yu Tian, Zhonghao Sun, Wenqian Wang, Hai Shang, Baoqi Wang, Di Deng, Guoxu Ma, Haifeng Wu, Nailiang Zhu, Xudong Xu, Guibo Sun and Xiaobo Sun

Molecules 2018, 23(1), 44; https://doi.org/10.3390/molecules23010044 - 10 Jan 2018

Cited by 7 | Viewed by 3999

Abstract

A series of novel oleanolic acid 3-O-β-d-glucuronopyranoside derivatives have been designed and synthesized. Biological evaluation has indicated that some of the synthesized compounds exhibit moderate to good activity against H₂O₂-induced injury in rat myocardial cells (H9c2). Particularly, derivative 28-N-isobutyl ursolic amide 3-O-β-d-galactopyranoside (8a) exhibited a greater protective effect than the positive control oleanolic acid 3-O-β-d-glucuronopyranoside, indicating that it possesses a great potential for further development as a cardiovascular disease modulator by structural modification. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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Review

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15 pages, 1690 KiB

Open AccessReview

Deep Learning in Drug Discovery and Medicine; Scratching the Surface

by Dibyendu Dana, Satishkumar V. Gadhiya, Luce G. St. Surin, David Li, Farha Naaz, Quaisar Ali, Latha Paka, Michael A. Yamin, Mahesh Narayan, Itzhak D. Goldberg and Prakash Narayan

Molecules 2018, 23(9), 2384; https://doi.org/10.3390/molecules23092384 - 18 Sep 2018

Cited by 56 | Viewed by 11490

Abstract

The practice of medicine is ever evolving. Diagnosing disease, which is often the first step in a cure, has seen a sea change from the discerning hands of the neighborhood physician to the use of sophisticated machines to use of information gleaned from biomarkers obtained by the most minimally invasive of means. The last 100 or so years have borne witness to the enormous success story of allopathy, a practice that found favor over earlier practices of medical purgatory and homeopathy. Nevertheless, failures of this approach coupled with the omics and bioinformatics revolution spurred precision medicine, a platform wherein the molecular profile of an individual patient drives the selection of therapy. Indeed, precision medicine-based therapies that first found their place in oncology are rapidly finding uses in autoimmune, renal and other diseases. More recently a new renaissance that is shaping everyday life is making its way into healthcare. Drug discovery and medicine that started with Ayurveda in India are now benefiting from an altogether different artificial intelligence (AI)—one which is automating the invention of new chemical entities and the mining of large databases in health-privacy-protected vaults. Indeed, disciplines as diverse as language, neurophysiology, chemistry, toxicology, biostatistics, medicine and computing have come together to harness algorithms based on transfer learning and recurrent neural networks to design novel drug candidates, a priori inform on their safety, metabolism and clearance, and engineer their delivery but only on demand, all the while cataloging and comparing omics signatures across traditionally classified diseases to enable basket treatment strategies. This review highlights inroads made and being made in directed-drug design and molecular therapy. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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20 pages, 3307 KiB

Open AccessReview

Enhancing the Delivery of Chemotherapeutics: Role of Biodegradable Polymeric Nanoparticles

by Jyoti Ahlawat, Gabriela Henriquez and Mahesh Narayan

Molecules 2018, 23(9), 2157; https://doi.org/10.3390/molecules23092157 - 27 Aug 2018

Cited by 80 | Viewed by 7511

Abstract

While pharmaceutical drugs have revolutionized human life, there are several features that limit their full potential. This review draws attention to some of the obstacles currently facing the use of chemotherapeutic drugs including low solubility, poor bioavailability and high drug dose. Overcoming these issues will further enhance the applicability and potential of current drugs. An emerging technology that is geared towards improving overall therapeutic efficiency resides in drug delivery systems including the use of polymeric nanoparticles which have found widespread use in cancer therapeutics. These polymeric nanoparticles can provide targeted drug delivery, increase the circulation time in the body, reduce the therapeutic indices with minimal side-effects, and accumulate in cells without activating the mononuclear phagocyte system (MPS). Given the inroads made in the field of nanodelivery systems for pharmaceutical applications, it is of interest to review and emphasize the importance of Polymeric nanocarrier system for drug delivery in chemotherapy. Full article

(This article belongs to the Special Issue Directed Drug Design and Molecular Therapy)

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