Drug Discovery and In Silico Techniques: A Mini-Review

Ahmad, Mohd Hassan Khurshid

doi:10.4172/2329-6674.1000123

Cited by 14 publications

(8 citation statements)

References 19 publications

(23 reference statements)

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“…The application of computational (in silico) methods in providing structural insights into the binding of small molecule inhibitors has gained prominence in the drug discovery process in recent years. Insights from computational reports can aid in the optimization of existing small molecule compounds to yield enhanced and improved novel small molecule inhibitors and eventually improve the overall efficiency of the drug discovery process . Computational approaches have been employed in the study of several conditions and for varying purposes including mutational studies and the identification of new inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Salifu

Agoni

Dokurugu

2019

J of Cellular Biochemistry

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Therapeutic targeting of the adenosine triphosphate (ATP) machinery of Mycobacterium tuberculosis (Mtb) has recently presented a potent and alternative measure to halt the pathogenesis of tuberculosis. This has been potentiated by the development of bedaquiline (BDQ), a novel small molecule inhibitor that selectively inhibits mycobacterial F1Fo‐ATP synthase by targeting its rotor c‐ring, resulting in the disruption of ATP synthesis and consequential cell death. Although the structural resolution of the mycobacterial C9 ring in co`mplex with BDQ provided the first‐hand detail of BDQ interaction at the c‐ring region of the ATP synthase, there still remains a need to obtain essential and dynamic insights into the mechanistic activity of this drug molecule towards crucial survival machinery of Mtb. As such, for the first time, we report an atomistic model to describe the structural dynamics that explicate the experimentally reported antagonistic features of BDQ in halting ion shuttling by the mycobacterial c‐ring, using molecular dynamics simulation and the Molecular Mechanics/Poisson‐Boltzmann Surface Area methods. Results showed that BDQ exhibited a considerably high ΔG while it specifically maintained high‐affinity interactions with Glu65B and Asp32B, blocking their crucial roles in proton binding and shuttling, which is required for ATP synthesis. Moreover, the bulky nature of BDQ induced a rigid and compact conformation of the rotor c‐ring, which impedes the essential rotatory motion that drives ion exchange and shuttling. In addition, the binding affinity of a BDQ molecule was considerably increased by the complementary binding of another BDQ molecule, which indicates that an increase in BDQ molecule enhances inhibitory potency against Mtb ATP synthase. Taken together, findings provide atomistic perspectives into the inhibitory mechanisms of BDQ coupled with insights that could enhance the structure‐based design of novel ATP synthase inhibitors towards the treatment of tuberculosis.

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Section: Introductionmentioning

confidence: 99%

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Salifu

Agoni

Dokurugu

2019

J of Cellular Biochemistry

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“…The targets can be identified at different levels, ranging from molecular to cellular to whole-organism levels [ 107 ]. Once these targets are identified, suitable molecules that interfere in its working can be identified [ 108 ]. In silico methods can facilitate faster drug development by making predictions for a large set of drug candidates without the need of chemically synthesizing each of the compounds [ 109 ].…”

Section: Models For Drug Discovery Against Ntmmentioning

confidence: 99%

Drug Resistance in Nontuberculous Mycobacteria: Mechanisms and Models

Saxena

Spaink

Forn-Cuní

2021

Biology

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The genus Mycobacteria comprises a multitude of species known to cause serious disease in humans, including Mycobacterium tuberculosis and M. leprae, the responsible agents for tuberculosis and leprosy, respectively. In addition, there is a worldwide spike in the number of infections caused by a mixed group of species such as the M. avium, M. abscessus and M. ulcerans complexes, collectively called nontuberculous mycobacteria (NTMs). The situation is forecasted to worsen because, like tuberculosis, NTMs either naturally possess or are developing high resistance against conventional antibiotics. It is, therefore, important to implement and develop models that allow us to effectively examine the fundamental questions of NTM virulence, as well as to apply them for the discovery of new and improved therapies. This literature review will focus on the known molecular mechanisms behind drug resistance in NTM and the current models that may be used to test new effective antimicrobial therapies.

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“…[16] In silico methods are extensively used for in vitro and in vivo studies to get the preliminary predictions of results of gross activities such as physicochemical characterization, toxicity properties, affinity to a target receptor or protein, the elucidation of absorption, distribution, metabolism and excretion. [17] In silico prediction of the toxicity is carried out to get a gross idea of the highest dose of paeonol that can be used in long-term studies without or less overt signs of toxicity. [22] In the current study, in silico prediction of the maximum tolerated human dose of paeonol was found to be 0.813 (log mg/kg/ day).…”

Section: Histopathological Studymentioning

confidence: 99%

In Silico and In Vivo Toxicological Evaluation of Paeonol

Adki

Murugesan

Kulkarni

2020

Chemistry & Biodiversity

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Paeonol is a phenolic compound reported for its various pharmacological activities such as antioxidant, antiinflammatory and antidiabetic activity. There are no systematic scientific reports on the in vivo toxicity of paeonol. So, the present work was designed to study in silico and in vivo toxicity of paeonol. In silico toxicity predictions were carried out using pkCSM, ProTox-II, pre-ADMET server and OSIRIS property explorer. Acute oral toxicity study of paeonol was carried out in female Sprague Dawley rats at a single dose of 300 mg/kg, 2000 mg/ kg and 5000 mg/kg. Animals were observed for toxicity signs and mortality for 14 days. Repeated dose oral toxicity study of paeonol was carried out in female and male Sprague Dawley rats at a dose of 50, 100 and 200 mg/kg body weight for 28 days. At the end of the study, hematological, biochemical and urine parameters were assessed. Histopathology of vital organs was also carried out. In silico toxicity study predicted that paeonol is non-toxic. The maximally tolerated dose of paeonol was found to be 5000 mg/kg in acute toxicity study in female rats. Paeonol was found to be safe at a dose of 50, 100 and 200 mg/kg in repeated dose toxicity study in male and female rats.

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Drug Discovery and In Silico Techniques: A Mini-Review

Cited by 14 publications

References 19 publications

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Drug Resistance in Nontuberculous Mycobacteria: Mechanisms and Models

In Silico and In Vivo Toxicological Evaluation of Paeonol

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