In Silico Drug Design of Benzothiadiazine Derivatives Interacting with Phospholipid Cell Membranes

Abstract

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and four of its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol at the liquid–crystal phase inside aqueous potassium chloride solution. We have elucidated the local structure of benzothiadiazine by means of microsecond molecular dynamics simulations of systems including a benzothiadiazine molecule or one of its derivatives. Such derivatives were obtained by the substitution of a single hydrogen site of benzothiadiazine by two different classes of chemical groups, one of them electron-donating groups (methyl and ethyl) and another one by electron-accepting groups (fluorine and trifluoromethyl). Our data have revealed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characteristics can vary significantly—they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10–70 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of characteristic lengths between 1.6 and 2.1 Å.

Discovering and targeting dynamic drugging pockets of the oncogene KRAS-G12D

“…The most suitable species obtained has been designed as DBD15-21-22 (see Figure 4A), since it is a DBD derivative, similar to some of those reported in Ref. 50 When GDP/GTP binds to the GDP/GTP binding pocket (Figure 5E), the O3 of guanine goes deep inside the pocket. DBD15-21-22 also has a guanine group, which is similar to GDP/GTP.…”

“…The most suitable species obtained has been designed as DBD15-21-22 (see Figure 4A), since it is a DBD derivative, similar to some of those reported in Ref. 50 .…”

Polyethylene Glycol (PEG‐200): An Efficient, Green and Biocompatible Reaction Medium for the Metal‐Free Synthesis of Functionalized 1,4‐Benzothiazines.

“…For example, methyl-3-ethyl-6,8-dimethyl-4Hbenzo[b] [1,4]-thiazine-2-carboxylate has been used as antioxidasnt, [4] antimicrobial, [4,5] antifungal, [4] 15-lypoxygenase inhibitor, [4] neuroleptics, [4] antirheumatic, [4] anticancer, [6] calcium antagonist, [4] cardiovascular, [4] antimalarial, [4] anthelmintic [4] agent. 1, 4-benzothiazine derivatives have reported to possess wide applications in medicinal chemistry, [7][8][9] for example it is used for the treatment of low blood sugar or as anti HIV agent [10] etc. Apart from the above, the 1, 4-benzothiazine is a fractional monetary unit of countless native pigments, dyestuffs and also available in one type of melanin, pheomelaqnin.…”

Discovery of a novel drug using lipid-based formulation targeting G12D-mutated KRAS4B through non-covalent bonds

“…DBD) is a bicyclic heterocyclic benzene derivative featuring amphiphilic properties and providing an opportunity as pharmacophores/warheads during the process of drug design. Its derivatives 39,40 have been long used in the human therapy as diuretic and antihypertensive agents, due to their widely biological pharmacological activities. 41,42 Lipid-based drug delivery systems, one of the most studied bioavailability enhancement technologies, are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs, 43 some chemical structures of some FDA approved drugs shown in Figure S2.…”