Ricardo J Ferreira

• BSc, MSc, PhD
• Associate Principal Scientist at RGDiscovery

P‐glycoprotein (P‐gp) has been considered an important molecular target in the reversal of multidrug resistance ( MDR ). As such, the development of P‐gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies for overcoming MDR . Since the identification of the P‐gp's role in MDR , se...

Background: From a dataset obtained by chemical derivatization of a macrocyclic diterpenic scaffold, in silico approaches identified which structural features correlate with experimental modulation of P-gp activity. Results/methodology: Ninety-two percent of the strongest MDR modulators were positively identified within the dataset by virtual scre...

The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction...

The membrane biophysical aspects by which multidrug resistance (MDR) relates with ABC transporters function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P-gp is inserted as determinant for the inc...

Multidrug-resistance (MDR) phenomena is a worldwide health concern. ABC efflux pumps as P-glycoprotein (P-gp) have been thoroughly studied in a frantic run to develop new efflux modulators capable to reverse MDR phenotypes. The study of efflux pumps has provided some key aspects on drug extrusion, however the answers could not be found solely on AB...

The onset of resistance to artemisinin for malaria treatment has stimulated the quest for novel antimalarial drugs. Herein, the gold(III) coordination complexes Aubipy [Au(bipy)Cl]+ (bipy = 2,2′-bipyridine), Auphen [Au(phen)Cl]+ (phen = phenanthroline), Auterpy [Au(terpy)Cl]2+ (terpy = 2,2′;6′,2″-terpyridine), and corresponding hydrolyzed species,...

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is associated with ACADM gene mutations, leading to an impaired function and/or structure of MCAD. Importantly, after import into the mitochondria, MCAD must incorporate a molecule of flavin adenine dinucleotide (FAD) per subunit and assemble into tetramers. However, the effect of MCAD a...

A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBSs) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in TMD1/NBD1 and another one in TMD2/NBD...

In this study, the impact of four P-gp mutations (G185V, G830V, F978A and ΔF335) on drug-binding and efflux-related signal-transmission mechanism was comprehensively evaluated in the presence of ligands within the drug-binding pocket (DBP), experimentally related with changes in their drug efflux profiles. The severe repacking of the transmembrane...

A medicinal chemistry approach combining in silico and in vitro methodologies was performed aiming at identifying and characterizing putative allosteric drug-binding sites (aDBS) at the interface of the transmembrane- and nucleotide-binding domains (TMD-NBD) of P-glycoprotein. Two aDBSs were identified, one in each NBD, by means of in silico fragme...

The modulation of drug efflux by P-glycoprotein (P-gp, ABCB1) represents one of the most promising approaches to overcome multidrug resistance (MDR) in cancer cells, however the mechanisms of drug specificity and signal-transmission are still poorly understood, hampering the development of more selective and efficient P-gp modulators. In this study...

Since the dawn of mankind natural sources have been explored due their valuable medicinal properties. Even in modern times several compounds are still being identified in the natural source(s) from which anti-microbial activity was originally isolated. However, the world of natural products is still the largest unexplored chemical space when compar...

In silico simulations of biological systems are of the significant importance to obtain insights on specific processes that experimental protocols have difficulty to elucidate. More particularly, and to ensure that a given molecule is able to reach its cellular target, the development of computational methods able to quickly estimate the cellular p...

Tuberculosis is an highly contagious disease still considered by the WHO as one of most infectious diseases worldwide. The therapeutic approach, used to prevent and treat tuberculosis targets the Mycobacterium tuberculosis complex, comprises a combination of drugs administrated for long periods of time, which, in many cases, could cause several adv...

Pedrolide (1), a diterpenoid with an unprecedented carbon skeleton, pedrolane, containing a bicycle[2.2.1]heptane system, is reported. This structural feature is hypothesized to involve an intramolecular cyclization, via Michael addition, and a ring contraction, via 1,2-alkyl shift or a Pinacol rearrangement of rings A and B, from a tigliane-type 5...

Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR...

The Gram-negative bacterial outer membrane poses a major obstacle to the development of much-needed antibiotics against drug-resistant infections. Its chemical composition and porin proteins differ from Gram-positive bacteria and mammalian cells, and heuristics developed for mammalian cell uptake apply poorly. Recently, machine-learning methods hav...

Naringenin (1), isolated from Euphorbia pedroi, was previously derivatized yielding compounds 2-13. In this study, aiming at expanding the pool of analogues of the flavanone core towards better multidrug resistance (MDR) reversal agents, alkylation reactions and chemical modification of the carbonyl moiety was performed (15-39). Compounds structure...

P-glycoprotein (P-gp) is a key efflux pump involved in cellular multidrug resistance (MDR), lowering the concentration of many anticancer drugs in tumor cells by pumping them into the extracellular milieu. While previous studies identified 1,4-dihydropyridines (DHP) as putative P-gp allosteric inhibitors, none reported the effect of stereochemistry...

P-glycoprotein (P-gp, ABCB1) overexpression is, currently, one of the most important multidrug resistance (MDR) mechanisms in tumor cells. Thus, modulating drug efflux by P-gp has become one of the most promising approaches to overcome MDR in cancer. Yet, more insights on the molecular basis of drug specificity and efflux-related signal transmissio...

Non-enveloped icosahedral double-stranded RNA (dsRNA) viruses possess multifunctional capsids required for their proliferation. Whereas protozoan/fungal dsRNA viruses have a relatively simple capsid structure, which suffices for the intracellular phase in their life cycle, metazoan dsRNA viruses have acquired additional structural features as an ad...

Background Multidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives 1–16 were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (17), a lathyrane-...

The development of multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. Several abietane diter-penes with antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone (AHR, 2). Several royleanone derivatives were prepared through hemi-synthesis...

Crossing the gram-negative bacterial membrane poses a major barrier to antibiotic development, as many small molecules that can biochemically inhibit key bacterial processes are rendered microbiologically ineffective by their poor cellular uptake. The outer membrane is the major permeability barrier for many drug-like molecules, and the chemical pr...

The occluded conformation suggested in a recent article that revealed a new inward-facing conformation for the human P-glycoprotein may not represent the closing of a gate region but instead an artifact derived from lateral compression in a too small sized nanodisc, used to stabilize the transmembrane domains of the transporter.

Python script incorporating an implicit membrane slab to correct polar solvation energies of membrane proteins. To be used together with g_mmpbsa. Developed for ABC transporters such as P-glycoprotein. Currently searching for collaborations to incorporate the implicit membrane approach from the Python code into the C source code of g_mmpbsa (thus u...

Crossing the gram-negative bacterial membrane poses a major barrier to antibiotic development, as many small molecules that can biochemically inhibit key bacterial processes are rendered microbiologically ineffective by their poor cellular uptake. The outer membrane is the major permeability barrier for many drug-like molecules, and the chemical pr...

The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2−8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, an ent-abietane diterpene, was derivatized by introduc...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Aim: Naringenin (1), isolated in large amount from the aerial parts of Euphorbia pedroi, was chemically derivatized to yield 18 imine derivatives (2-19) and three alkylated derivatives through a Mannich-type reaction (20-22) that were tested as multidrug resistance (MDR) reversers in cancer cells. Results/methodology: While hydrazone (2-4) and azi...

Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein (BCRP), based on the recently published crystallograph...

Multidrug resistance (MDR) in cancer is one of the major impairments in the success of chemotherapy. The main objective of this work was the identification and optimization of MDR reversers, derived from Euphorbia species, and to gain insights on the drug efflux mechanism by P-gp. The phytochemical study of Euphorbia pedroi yielded four new diterpe...

This expansive and practical textbook contains organic chemistry experiments for teaching in the laboratory at the undergraduate level covering a range of functional group transformations and key organic reactions.The editorial team have collected contributions from around the world and standardized them for publication. Each experiment will explor...

http://pubs.acs.org/doi/suppl/10.1021/acs.jctc.5b00652

The failure of chemotherapeutics in cancer is mainly imputed to multidrug resistance (MDR). Among several proposed approaches to overcome MDR, the modulation of P-glycoprotein (Pgp) is the most highlighted [1]. Another valuable strategy is to take advantage of the collateral sensitivity effect, where some compounds may selectively exert a more pron...

Euphorbia species have been a source of a great variety of structurally unique macrocyclic diterpenes, which have been reported to be potent modulators of multidrug resistance (MDR) in cancer cell lines [1]. MDR is a complex and multifactorial phenomenon that frequently hamper the successful treatment of cancer diseases. One of the most relevant me...

One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents—multidrug resistance (MDR). As P‐glycoprotein (P‐gp) is one of the most studied ATP‐dependent efflux pumps that are frequently involved in drug efflux from cancer cells, t...

P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype expressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism and drug-binding sites. This information is, however, scattered through di...

This paper focuses on the importance of the intermediate linker sequence for the stabilization of the cytoplasmic portion of murine P-glycoprotein, an ABC transporter involved in Multidrug Resistance (MDR) in cancer. Three putative protein-protein interaction areas were predicted to exist, two of them next to the C-terminal nucleotide-binding domai...

The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to twelve ester derivatives (2-13) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 1-14 was evaluated through a combination of transport and chemosensitivity assays, using the L5178 mouse T lymphoma ce...

P-glycoprotein is one of the best studied transmembranar proteins directly related with multidrug resistance phenomenon. Using a refined P-gp structure recently published by our group, new docking studies have identified three distinct binding sites: two for substrates (H- and R-sites) and one for modulators (Modulator-site), which are in perfect a...

Multidrug resistance is a major hurdle for the success of cancer chemotherapy. The main cause for this phenomenon is attributed to the overexpression of the efflux pump, P-glycoprotein (P-gp). A small library of novel bioactive macrocyclic lathyrane-type diterpene derivatives was developed to discover a selective P-gp reversal agent. In this way, a...

Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of featur...

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (P-glycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore modeling and structure-activity relationships studies of sixteen macrocyclic diterpenes and poly...

Cancer is one of the most prevalent and challenging diseases in the current century. Despite the advances in medical and in pharmacological treatment, some types of cancer develop multidrug resistance, often related to the increased expression of P-glycoprotein (P-gp) by cancer cells, thus contributing for the failure of chemotherapeutic treatments...

Cancer is one of the diseases with increased prevalence in the 21st century. Since the 1970s that a class of transmembranar proteins called ABC transporters are known, being P-Glycoprotein (Pgp) the most representative member. They are often involved in the efflux of drugs preventing their accumulation in the cytoplasm and thus decreasing the thera...

P-glycoprotein (P-gp) is the most representative member of the ABC transmembranar transporter superfamily, often implicated in the multidrug-resistance phenomenon (MDR) [1]. Several models have been proposed for the efflux mechanism, namely the hydrophobic pore, the flipase model and, more recently, the hydrophobic vacuum-cleaner model. Using the...

Multidrug-resistance phenomenon (MDR) to anti-cancer drugs is one of the most serious obstacles in the success of a chemotherapeutic treatment. P-glycoprotein (P-gp) is often implied in the efflux of drugs as anthracyclins, vinca alkaloids, taxanes and other non-related drug, lowering the effective concentration of such drugs in the cytoplasmatic c...