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Computational Drug Discovery and Development Along With Their Applications in the Treatment of Women-Associated Cancers
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
Rahul Kumar, Rakesh Kumar, Harsh Goel, Somorjit Singh Ningombam, Pranay Tanwar
LBDD is another popular method for drug designing, which usually works in the absence of 3D structure of a target protein. The known ligand molecules are investigate to understand the structural and physio-chemical properties which can correlate with the desired pharmacological activity. It is based on the assumption of similar property principle; those compounds display identical structures have similar biological responses upon interactions with the target [31]. This method can also predict novel molecular structures with features facilitating the interactions with the target molecule. 3D QSAR and pharmacophore modelling are the most prominent and commonly used methods in LBDD process that can provide insights into the nature of interactions between drug target and the ligand molecule, thus provide a predictive model suitable for lead compound optimization [32–33].
Structure of Matter
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
The strength of the bonds existing between subgroups of particles depends upon whether the forces are within the nucleus, inside the atom, between atoms or between molecules. The rest of this chapter will deal with atomic and molecular structures. The structure of the nucleus will be considered in Chapter 2.
Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Anticholinesterase drugs inhibit the active site of acetylcholinesterase reversibly or irreversibly, depending on the interactions with the active site. The two main groups of anticholinesterases include carbamates and organophosphorus compounds. The lead compound for the carbamate inhibiters was sourced from the natural product physostigmine, which was discovered in 1864 as a product from the poisonous calabar bean from West Africa; structure determined in 1925. This compound is still used clinically to treat glaucoma. SAR studies show that the carbamate group is essential to the activity, the benzene ring is important, and the pyrollidine nitrogen is ionised at blood pH; crucial for binding to anionic residues in the active site. The carbamate group is crucial for the inhibitory properties of physostigmine. The mechanism for hydrolysis produces a stable carbonyl intermediate which is the rate-determining step. Molecular structures for some of these compounds are given in Figure 6 of the Supporting Material∗. Due to serious side-effects, its medical uses are limited, so analogues have been made that retain these important features.
A more specific concept of a pharmacophore to better rationalize drug design, tailor patient therapy, and tackle bacterial resistance to antibiotics
Published in Expert Opinion on Drug Discovery, 2022
Jessica Rubí Morán Díaz, Juan Alberto Guevara-Salazar, Roberto Issac Cuevas Hernández, José Guadalupe Trujillo Ferrara
A pharmacophore is the minimum portion of a molecular structure that causes a therapeutic effect in evidence-based medicine. The concept of a pharmacophore should be expanded to include the analysis of how modifications in molecular structure affect the binding orientation of a compound and changes in biological activity. Besides SAR/QSAR, docking, and molecular dynamics analyses, another useful in silico technique for tailored approaches to drug development is the fingerprint descriptor of the chemical and structural information of binding sites, which could help to generate favorable interactions. Machine learning methods can be utilized to explore the relation of bioactivity data with fingerprint descriptors. These insights will help to individualize patient therapy. Hence, a pharmacophore can be considered as a set of atoms that is distinguishable by its specific connectivity, configuration, and conformation and that has the necessary steric and electronic characteristics to ensure the desirable supramolecular interaction with a certain receptor to activate or block its biological response.
Strategies for targeting the cardiac sarcomere: avenues for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Joshua B. Holmes, Chang Yoon Doh, Ranganath Mamidi, Jiayang Li, Julian E. Stelzer
The first step of the hypothesis-driven drug discovery process entails a detailed understanding of the mode of drug action on molecular structures and its effects on ligand interaction. One traditional method of drug discovery involves testing a large, random number of compounds using high-content or high-throughput screening to identify lead compounds more quickly [10]. An abundant amount of experimental data on drug activity, specificity, and/or toxicity can be collected using a diverse array of cellular and chemical assays this way [11]. In addition, phenotypic screening can identify ‘first-in-class’ drugs that would have otherwise been unknown [12]. Recent innovations in high-throughput screening that use contractile-force based platforms [13,14], functional assays of skeletal muscle [15], and time-resolved fluorescence resonance energy transfer (TR-FRET) [16] have allowed researchers to target sarcomeric proteins. High-throughput screening has also been successful in discovering novel small molecule inhibitors of cardiac hypertrophy [17]. These include various screening systems like induced pluripotent stem cell (iPSC)-derived cardiomyocytes [18] and biomimetic cardiac microsystems [19]. High-throughput crystallography techniques can also aid in structure determination [20].
Recent CPP-based applications in medicine
Published in Expert Opinion on Drug Delivery, 2019
The CPP field started in 1988, when Frankel et al. characterized intrinsic cell-penetrating property of HIV transactivator of transcription (Tat) in 1988 [1,2]. CPPs are typically short peptides of <30 amino acids that can pass through cell membranes and they are exclusively discussed and studied in the context of drug delivery, i.e. transport of cargo molecules. Various types of cargo have been effectively transported through biological barriers using CPPs, including small molecular drug molecules, peptides, proteins, nucleic acid, nanoparticles, imaging agents [3]. The ‘classical’ way is that cargoes are attached to CPPs by covalent conjugation or by fusion of the (peptide) cargo with the CPP (Figure 1). This has the advantage of obtaining well-defined molecular structures as therapeutic entities. In recent years, more prevalent method is through the utilization of nanotechnology, by incorporating several functionalities besides the cell penetration into a drug nanoplatform (Figure 1). Both of these approaches are existing in parallel, having their own distinct applications [4] and both of these research directions with recent examples are presented in the following review.