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      Synthesis, comparative docking, and pharmacological activity of naproxen amino acid derivatives as possible anti-inflammatory and analgesic agents

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          Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative.

          Methods: The structure of compounds 5–20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter- and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity.

          Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them ( 5–16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds.

          Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.

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          Most cited references 32

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          Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters

          Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and ΔH f for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in ΔH f decreased by about 10 %; for organic solids, the AUE in ΔH f dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol-1 in PM6 and 10.8 kcal/mol-1 in PM7 to 3.8 kcal/mol-1. The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved. Electronic supplementary material The online version of this article (doi:10.1007/s00894-012-1667-x) contains supplementary material, which is available to authorized users.
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            P-glycoprotein Inhibition for Optimal Drug Delivery

             Md. Amin (2013)
            P-glycoprotein (P-gp), an efflux membrane transporter, is widely distributed throughout the body and is responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. Hundreds of structurally diverse therapeutic agents are substrates to it and it impedes the absorption, permeability, and retention of the drugs, extruding them out of the cells. It is overexpressed in cancer cells and accountable for obstructing cell internalization of chemotherapeutic agents and for developing transporter mediated resistance by cancer cells during anti-tumor treatments. As it jeopardizes the success of drug delivery and cancer targeting, strategies are being developed to overcome P-gp mediated drug transport. This concise review represents a brief discussion on P-gp mediated drug transport and how it hinders the success of various therapies. Its main focus is on various strategies used to tackle this curb in the field of drug delivery and targeting.
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              Computational methods for the prediction of 'drug-likeness'

              Recently, one of the key trends in the pharmaceutical industry has been the integration of what have traditionally been considered 'development' activities into the early phases of drug discovery. The aim of this paradigm shift is the prompt identification and elimination of candidate molecules that are unlikely to survive later stages of discovery and development. In this review, the authors examine the growing role that is being played by computational methods in this filtering process, with a particular focus on the prediction of intestinal absorption and blood-brain barrier penetration.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                24 May 2019
                : 13
                : 1773-1790
                [1 ]Chemistry Department, Faculty of Science, Al-Azhar University (Boys' Branch) , Nasr City, Cairo, Egypt
                [2 ]King Abdulaziz University , Jeddah 21589, Saudi Arabia
                [3 ]Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre , Dokki, Giza 12622, Egypt
                [4 ]Department of Pharmacology, National Research Centre , Giza, Egypt
                Author notes
                Correspondence: Ahmed A ElhenawyChemistry Department, Faculty of Science, Al-Azhar University (Boys' Branch) , Nasr City, Cairo11884, EgyptTel +96 650 867 8586Email elhenawy_sci@ 123456hotmail.com
                © 2019 Elhenawy et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 3, References: 47, Pages: 18
                Original Research


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