Abstract:A series of five benzimidazole-based
compounds were identified using a machine learning algorithm as potential
inhibitors of the respiratory syncytial virus (RSV) fusion protein.
These compounds were synthesized, and compound 2 in particular
exhibited excellent in vitro potency with an EC50 value of 5 nM. This new scaffold was then further refined
leading to the identification of compound 44, which exhibited
a 10-fold improvement in activity with an EC50 value of
0.5 nM.
“…During the last years, a number of RSV glycoprotein inhibitors have been disclosed and experimentally investigated by means of X-ray crystallographic analysis, with most of them being endowed with a benzothiazole core or other heterocyclic rings, bioisosteres of the benzimidazole one, as shown in Figure 1 [13][14][15][16][17][18][19][20][21][22][23][24][25].…”
Section: Exploring the X-ray Crystallographic Data Of Known Preclinical Fusion Inhibitorsmentioning
confidence: 99%
“…However, only a few of them, namely JNJ-2408068 (R-170591), BMS-433771, and TMC353121 (Figure 1), have been progressed to late stages of (pre)clinical development but have been discontinued after a negative outcome, mainly due to their unfavorable pharmaceutical properties or early safety findings [14,15]. The intense efforts leading to the discover of these molecules have encouraged the research of new analogues, mainly exploiting the bioisosteric approach but also of structurally distinct core scaffolds that allowed for the identification of very promising RSV fusion inhibitors [9][10][11][12][13][14][15][16][17]. The fusion inhibitor GS-5806 (Presatovir), characterized by a pyrazole-pyrimidine core structure, has recently completed Phase II evaluation and has been shown to provide potential benefit only to patients with upper respiratory tract infection (URTI).…”
Section: Introductionmentioning
confidence: 99%
“…Since 2017, the indole derivative JNJ-53718678 (Rilematovir) has ranked in the top position among RSV fusion inhibitors in terms of advancement through clinical trials [19], as it is undergoing Phase II evaluation in adults and infants for therapy of RSV infections (ClinicalTrials.gov Identifier NCT03379675, NCT03656510, NCT04056611). Its promising The intense efforts leading to the discover of these molecules have encouraged the research of new analogues, mainly exploiting the bioisosteric approach but also of structurally distinct core scaffolds that allowed for the identification of very promising RSV fusion inhibitors [9][10][11][12][13][14][15][16][17]. The fusion inhibitor GS-5806 (Presatovir), characterized by a pyrazolepyrimidine core structure, has recently completed Phase II evaluation and has been shown to provide potential benefit only to patients with upper respiratory tract infection (URTI).…”
Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents.
“…During the last years, a number of RSV glycoprotein inhibitors have been disclosed and experimentally investigated by means of X-ray crystallographic analysis, with most of them being endowed with a benzothiazole core or other heterocyclic rings, bioisosteres of the benzimidazole one, as shown in Figure 1 [13][14][15][16][17][18][19][20][21][22][23][24][25].…”
Section: Exploring the X-ray Crystallographic Data Of Known Preclinical Fusion Inhibitorsmentioning
confidence: 99%
“…However, only a few of them, namely JNJ-2408068 (R-170591), BMS-433771, and TMC353121 (Figure 1), have been progressed to late stages of (pre)clinical development but have been discontinued after a negative outcome, mainly due to their unfavorable pharmaceutical properties or early safety findings [14,15]. The intense efforts leading to the discover of these molecules have encouraged the research of new analogues, mainly exploiting the bioisosteric approach but also of structurally distinct core scaffolds that allowed for the identification of very promising RSV fusion inhibitors [9][10][11][12][13][14][15][16][17]. The fusion inhibitor GS-5806 (Presatovir), characterized by a pyrazole-pyrimidine core structure, has recently completed Phase II evaluation and has been shown to provide potential benefit only to patients with upper respiratory tract infection (URTI).…”
Section: Introductionmentioning
confidence: 99%
“…Since 2017, the indole derivative JNJ-53718678 (Rilematovir) has ranked in the top position among RSV fusion inhibitors in terms of advancement through clinical trials [19], as it is undergoing Phase II evaluation in adults and infants for therapy of RSV infections (ClinicalTrials.gov Identifier NCT03379675, NCT03656510, NCT04056611). Its promising The intense efforts leading to the discover of these molecules have encouraged the research of new analogues, mainly exploiting the bioisosteric approach but also of structurally distinct core scaffolds that allowed for the identification of very promising RSV fusion inhibitors [9][10][11][12][13][14][15][16][17]. The fusion inhibitor GS-5806 (Presatovir), characterized by a pyrazolepyrimidine core structure, has recently completed Phase II evaluation and has been shown to provide potential benefit only to patients with upper respiratory tract infection (URTI).…”
Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents.
“…A lead optimization strategy based on a machine learning algorithm led to novel compounds integrating the popular benzimidazole scaffold. 80 The most active analogue in this series demonstrated subnanomolar in vitro potency comparable to JNJ-53718678 (EC 50 = 0.5 vs 0.9 nM) against wild-type RSV with a CC 50 > 20 μM; however, it was significantly less potent against the clinically reported viral escape mutant D489E, emphasizing the need for RSV combination therapy rather than monotherapy. Fig.…”
“…FRESH made use of structural information and ligand-based methods, and also proved useful when only limited structural information was available. The possibility to create a list of proposed active compounds using only a machine learning/Bayesian model without the input of structural biology represents an exciting and successful feature of FRESH 11,13,45 as well as an area for continued investigation. One of the limitations of FRESH is the requirement of a preexisting and broad activity profile to give predictive capability to the models.…”
As a result of the rapidly increasing cost of drug development, efficient methods for early identification of compounds with a high probability of clinical success are needed. Herein, we describe a cheminformatics protocol which dramatically increases quality candidate identification and should reduce the attrition rate of compounds entering the clinic, increasing the cost-effectiveness of drug development. Against the oncology target phosphatidylinositol 3-kinase α, all five compounds synthesized from the protocol were found to have low nanomolar activity. We therefore propose that our protocol can be used as a tool for reducing the synthetic burden required for hit-to-lead optimization.
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